
Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality.
Kim Il-Kug,Kim Kangsan,Lee Eunhyeong,Oh Dong Sun,Park Chan Soon,Park Seongyeol,Yang Jee Myung,Kim Ju-Hee,Kim Hyung-Seok,Shima David T,Kim Jeong Hoon,Hong Seok Ho,Cho Young Hyun,Kim Young Hoon,Park Jong Bae,Koh Gou Young,Ju Young Seok,Lee Heung Kyu,Lee Seungjoo,Kim Injune
The Journal of experimental medicine
High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing -deficient abnormal vessels with high Sox7 levels but promoted it by regressing -deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG.
10.1084/jem.20170123
Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
Cancer cell
We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.
10.1016/j.ccell.2014.11.002
Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers.
Ichimura Koichi,Narita Yoshitaka,Hawkins Cynthia E
Acta neuropathologica
Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies.
10.1007/s00401-015-1439-7
A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.
O'Rourke Donald M,Nasrallah MacLean P,Desai Arati,Melenhorst Jan J,Mansfield Keith,Morrissette Jennifer J D,Martinez-Lage Maria,Brem Steven,Maloney Eileen,Shen Angela,Isaacs Randi,Mohan Suyash,Plesa Gabriela,Lacey Simon F,Navenot Jean-Marc,Zheng Zhaohui,Levine Bruce L,Okada Hideho,June Carl H,Brogdon Jennifer L,Maus Marcela V
Science translational medicine
We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.
10.1126/scitranslmed.aaa0984
A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma.
Barnes J Matthew,Kaushik Shelly,Bainer Russell O,Sa Jason K,Woods Elliot C,Kai FuiBoon,Przybyla Laralynne,Lee Mijeong,Lee Hye Won,Tung Jason C,Maller Ori,Barrett Alexander S,Lu Kan V,Lakins Jonathon N,Hansen Kirk C,Obernier Kirsten,Alvarez-Buylla Arturo,Bergers Gabriele,Phillips Joanna J,Nam Do-Hyun,Bertozzi Carolyn R,Weaver Valerie M
Nature cell biology
Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.
10.1038/s41556-018-0183-3
Sox2: masterminding the root of cancer.
Tam Wai Leong,Ng Huck Hui
Cancer cell
The transcription factor Sox2 is a master regulator that maintains stemness in embryonic stem cells and neural stem cells. Using elegant lineage tracing strategies and genetic reporter mouse models, two studies (one of which is by Vanner and colleagues in this issue of Cancer Cell) now demonstrate that rare Sox2-expressing cells are the founding cancer stem cell population driving tumor initiation and therapy resistance.
10.1016/j.ccr.2014.06.024
Histone epiproteomic profiling distinguishes oligodendroglioma, IDH-mutant and 1p/19q co-deleted from IDH-mutant astrocytoma and reveals less tri-methylation of H3K27 in oligodendrogliomas.
Feller C,Felix M,Weiss T,Herold-Mende C,Zhang F,Kockmann T,Sahm F,Aebersold R,von Deimling A,Reuss D E
Acta neuropathologica
10.1007/s00401-019-02096-8
Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development.
Binder Zev A,Thorne Amy Haseley,Bakas Spyridon,Wileyto E Paul,Bilello Michel,Akbari Hamed,Rathore Saima,Ha Sung Min,Zhang Logan,Ferguson Cole J,Dahiya Sonika,Bi Wenya Linda,Reardon David A,Idbaih Ahmed,Felsberg Joerg,Hentschel Bettina,Weller Michael,Bagley Stephen J,Morrissette Jennifer J D,Nasrallah MacLean P,Ma Jianhui,Zanca Ciro,Scott Andrew M,Orellana Laura,Davatzikos Christos,Furnari Frank B,O'Rourke Donald M
Cancer cell
We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR mutants, corroborated in mice bearing intracranial tumors expressing EGFR and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR mutation in glioblastoma, postulating EGFR as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.
10.1016/j.ccell.2018.06.006
Daam2 driven degradation of VHL promotes gliomagenesis.
Zhu Wenyi,Krishna Saritha,Garcia Cristina,Lin Chia-Ching John,Mitchell Bartley D,Scott Kenneth L,Mohila Carrie A,Creighton Chad J,Yoo Seung-Hee,Lee Hyun Kyoung,Deneen Benjamin
eLife
Von Hippel-Landau (VHL) protein is a potent tumor suppressor regulating numerous pathways that drive cancer, but mutations in VHL are restricted to limited subsets of malignancies. Here we identified a novel mechanism for VHL suppression in tumors that do not have inactivating mutations. Using developmental processes to uncover new pathways contributing to tumorigenesis, we found that Daam2 promotes glioma formation. Protein expression screening identified an inverse correlation between Daam2 and VHL expression across a host of cancers, including glioma. These in silico insights guided corroborating functional studies, which revealed that Daam2 promotes tumorigenesis by suppressing VHL expression. Furthermore, biochemical analyses demonstrate that Daam2 associates with VHL and facilitates its ubiquitination and degradation. Together, these studies are the first to define an upstream mechanism regulating VHL suppression in cancer and describe the role of Daam2 in tumorigenesis.
10.7554/eLife.31926
Novel FGFR2-INA fusion identified in two low-grade mixed neuronal-glial tumors drives oncogenesis via MAPK and PI3K/mTOR pathway activation.
Jain Payal,Surrey Lea F,Straka Joshua,Luo Minjie,Lin Fumin,Harding Brian,Resnick Adam C,Storm Phillip B,Buccoliero Anna Maria,Santi Mariarita,Li Marilyn M,Waanders Angela J
Acta neuropathologica
10.1007/s00401-018-1864-5
Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival.
Zhu Zhe,Khan Muhammad Amir,Weiler Markus,Blaes Jonas,Jestaedt Leonie,Geibert Madeleine,Zou Peng,Gronych Jan,Bernhardt Olga,Korshunov Andrey,Bugner Verena,Lichter Peter,Radlwimmer Bernhard,Heiland Sabine,Bendszus Martin,Wick Wolfgang,Liu Hai-Kun
Cell stem cell
Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx(+) cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx(+) cells can self-renew and generate Tlx(-) tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis.
10.1016/j.stem.2014.04.007
MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.
Gallo Marco,Coutinho Fiona J,Vanner Robert J,Gayden Tenzin,Mack Stephen C,Murison Alex,Remke Marc,Li Ren,Takayama Naoya,Desai Kinjal,Lee Lilian,Lan Xiaoyang,Park Nicole I,Barsyte-Lovejoy Dalia,Smil David,Sturm Dominik,Kushida Michelle M,Head Renee,Cusimano Michael D,Bernstein Mark,Clarke Ian D,Dick John E,Pfister Stefan M,Rich Jeremy N,Arrowsmith Cheryl H,Taylor Michael D,Jabado Nada,Bazett-Jones David P,Lupien Mathieu,Dirks Peter B
Cancer cell
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
10.1016/j.ccell.2015.10.005
Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation.
Shingu Takashi,Ho Allen L,Yuan Liang,Zhou Xin,Dai Congxin,Zheng Siyuan,Wang Qianghu,Zhong Yi,Chang Qing,Horner James W,Liebelt Brandon D,Yao Yu,Hu Baoli,Chen Yiwen,Fuller Gregory N,Verhaak Roeland G W,Heimberger Amy B,Hu Jian
Nature genetics
Stem cells, including cancer stem cells (CSCs), require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal co-deletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to the expansion of these cells in their subventricular zone (SVZ) niches but fails to maintain stemness outside the SVZ. We discovered that Qki is a major regulator of NSC stemness. Qk deletion on a Pten; Trp53 background helps NSCs maintain their stemness outside the SVZ in Nes-CreER; Qk; Pten; Trp53 mice, which develop glioblastoma with a penetrance of 92% and a median survival time of 105 d. Mechanistically, Qk deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside niches. Thus, downregulation of endolysosome levels by Qki loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside their niches.
10.1038/ng.3711
Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy.
Science translational medicine
The heterogeneous expression of tumor-associated antigens limits the efficacy of chimeric antigen receptor (CAR)-redirected T cells (CAR-Ts) for the treatment of glioblastoma (GBM). We have found that chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed in 67% of the GBM specimens with limited heterogeneity. CSPG4 is also expressed on primary GBM-derived cells, grown in vitro as neurospheres (GBM-NS), which recapitulate the histopathology and molecular characteristics of primary GBM. CSPG4.CAR-Ts efficiently controlled the growth of GBM-NS in vitro and in vivo upon intracranial tumor inoculation. Moreover, CSPG4.CAR-Ts were also effective against GBM-NS with moderate to low expression of CSPG4. This effect was mediated by the in vivo up-regulation of CSPG4 on tumor cells, induced by tumor necrosis factor-α (TNFα) released by the microglia surrounding the tumor. Overall, the constitutive and TNFα-inducible expression of CSPG4 in GBM may greatly reduce the risk of tumor cell escape observed when targeted antigens are heterogeneously expressed on tumor cells.
10.1126/scitranslmed.aao2731
Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.
Nature genetics
Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.
10.1038/ng.2925
The cyclin-like protein Spy1 regulates growth and division characteristics of the CD133+ population in human glioma.
Lubanska Dorota,Market-Velker Brenna A,deCarvalho Ana C,Mikkelsen Tom,Fidalgo da Silva Elizabeth,Porter Lisa A
Cancer cell
The heterogeneity of brain cancers, as most solid tumors, complicates diagnosis and treatment. Identifying and targeting populations of cells driving tumorigenesis is a top priority for the cancer biology field. This is not a trivial task; considerable variance exists in the driving mutations, identifying markers, and evolutionary pressures influencing initiating cells in different individual tumors. Despite this, the ability to self-renew and differentiate must be conserved to reseed a heterogeneous tumor mass. Focusing on one example of a tumor-initiating cell population, we demonstrate that the atypical cyclin-like protein Spy1 plays a role in balancing the division properties of glioma cells with stemness properties. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer.
10.1016/j.ccr.2013.12.006
A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma.
El-Habr Elias A,Dubois Luiz G,Burel-Vandenbos Fanny,Bogeas Alexandra,Lipecka Joanna,Turchi Laurent,Lejeune François-Xavier,Coehlo Paulo Lucas Cerqueira,Yamaki Tomohiro,Wittmann Bryan M,Fareh Mohamed,Mahfoudhi Emna,Janin Maxime,Narayanan Ashwin,Morvan-Dubois Ghislaine,Schmitt Charlotte,Verreault Maité,Oliver Lisa,Sharif Ariane,Pallud Johan,Devaux Bertrand,Puget Stéphanie,Korkolopoulou Penelope,Varlet Pascale,Ottolenghi Chris,Plo Isabelle,Moura-Neto Vivaldo,Virolle Thierry,Chneiweiss Hervé,Junier Marie-Pierre
Acta neuropathologica
Cell populations with differing proliferative, stem-like and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios, and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. Our findings support an active participation of metabolic variations in the genesis of tumor heterogeneity.
10.1007/s00401-016-1659-5
ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma.
Koschmann Carl,Calinescu Anda-Alexandra,Nunez Felipe J,Mackay Alan,Fazal-Salom Janet,Thomas Daniel,Mendez Flor,Kamran Neha,Dzaman Marta,Mulpuri Lakshman,Krasinkiewicz Johnathon,Doherty Robert,Lemons Rosemary,Brosnan-Cashman Jacqueline A,Li Youping,Roh Soyeon,Zhao Lili,Appelman Henry,Ferguson David,Gorbunova Vera,Meeker Alan,Jones Chris,Lowenstein Pedro R,Castro Maria G
Science translational medicine
Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.
10.1126/scitranslmed.aac8228
CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism.
Science advances
Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67's interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: (catalytic antagonist of Polycomb; official gene name: ). We map inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As expression is regulated through DNA methylation/demethylation, we propose as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.
10.1126/sciadv.aax2887
An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
Cancer cell
Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.
10.1016/j.ccell.2016.09.008
Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors.
Brandenburg Susan,Müller Annett,Turkowski Kati,Radev Yordan T,Rot Sergej,Schmidt Christin,Bungert Alexander D,Acker Güliz,Schorr Anne,Hippe Andreas,Miller Kelly,Heppner Frank L,Homey Bernhard,Vajkoczy Peter
Acta neuropathologica
Myeloid cells are an essential part of the glioblastoma microenvironment. However, in brain tumors the function of these immune cells is not sufficiently clarified. In our study, we investigated differential pro-angiogenic activities of resident microglia and peripheral macrophages and their impact on glioma vascularization and progression. Our data demonstrate stable accumulation of microglia/macrophages during tumor growth. These cells often interact with tumor blood vessels correlating with vascular remodeling. Here, we identified resident microglia as well as peripheral macrophages as part of the perivascular niche, primarily contacting endothelial cells. We found overexpression of a variety of pro-angiogenic molecules within freshly isolated microglia/macrophages from glioma. CXCL2, until now a poorly described chemokine, was strongly up-regulated and showed better angiogenic activity than VEGF in vitro. Blocking the CXCL2-CXCR2 signaling pathway resulted in considerably diminished glioma sizes. Additionally, the importance of microglia/macrophages in tumor angiogenesis was confirmed by depletion of these cells in vivo. Vessel density decreased by 50% leading to significantly smaller tumor volumes. Remarkably, selective reduction of resident microglia affected tumoral vessel count comparable to ablation of the whole myeloid cell fraction. These results provide evidence that resident microglia are the crucial modulatory cell population playing a central role in regulation of vascular homeostasis and angiogenesis in brain tumors. Thus, resident microglia represent an alternative source of pro-angiogenic growth factors and cytokines.
10.1007/s00401-015-1529-6
Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma.
Cancer cell
While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.
10.1016/j.ccell.2017.10.016
The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells.
Liu Yinxing,Gilbert Misty R,Kyprianou Natasha,Rangnekar Vivek M,Horbinski Craig
Acta neuropathologica
Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild type, those that express more Par-4 have significantly longer median survival (18.4 vs. 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect.
10.1007/s00401-014-1334-7
A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.
Huang Yujie,Rajappa Prajwal,Hu Wenhuo,Hoffman Caitlin,Cisse Babacar,Kim Joon-Hyung,Gorge Emilie,Yanowitch Rachel,Cope William,Vartanian Emma,Xu Raymond,Zhang Tuo,Pisapia David,Xiang Jenny,Huse Jason,Matei Irina,Peinado Hector,Bromberg Jacqueline,Holland Eric,Ding Bi-Sen,Rafii Shahin,Lyden David,Greenfield Jeffrey
The Journal of clinical investigation
Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.
10.1172/JCI86443
Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma.
Science advances
A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
10.1126/sciadv.aau5935
Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties.
Chen Yi-Hsien,McGowan Lucy D'Agostino,Cimino Patrick J,Dahiya Sonika,Leonard Jeffrey R,Lee Da Yong,Gutmann David H
Cell reports
The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133(+) multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment.
10.1016/j.celrep.2015.02.041
ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.
Agnihotri Sameer,Burrell Kelly,Buczkowicz Pawel,Remke Marc,Golbourn Brian,Chornenkyy Yevgen,Gajadhar Aaron,Fernandez Nestor A,Clarke Ian D,Barszczyk Mark S,Pajovic Sanja,Ternamian Christian,Head Renee,Sabha Nesrin,Sobol Robert W,Taylor Michael D,Rutka James T,Jones Chris,Dirks Peter B,Zadeh Gelareh,Hawkins Cynthia
Cancer discovery
UNLABELLED:Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. SIGNIFICANCE:Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window.
10.1158/2159-8290.CD-14-0157
Lack of H3K27 trimethylation is associated with 1p/19q codeletion in diffuse gliomas.
Filipski Katharina,Braun Yannick,Zinke Jenny,Roller Bastian,Baumgarten Peter,Wagner Marlies,Senft Christian,Zeiner Pia S,Ronellenfitsch Michael W,Steinbach Joachim P,Plate Karl H,Gasparoni Gilles,Mittelbronn Michel,Capper David,Harter Patrick N
Acta neuropathologica
10.1007/s00401-019-02025-9
Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment.
The Journal of clinical investigation
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor. They show that the oncometabolite 2-hydroxyglutarate (2HG), generated by mutated forms of isocitrate dehydrogenase (IDH1 and IDH2), reduces the expression of STAT1, thereby limiting the production of the chemokines CXCL9 and CXCL10. As a result, IDH1-mutated tumors are less effectively infiltrated by CD8+ T cells, contributing to tumor escape. Finally, in mice harboring syngeneic gliomas, an inhibitor of 2HG synthesis complemented vaccination to ameliorate tumor control. Understanding how to increase immune infiltration of gliomas represents a key first step in achieving tumor destruction through immunotherapy.
10.1172/JCI93565
A niche role for periostin and macrophages in glioblastoma.
Squadrito Mario Leonardo,De Palma Michele
Nature cell biology
Macrophages facilitate tumour progression, but it is unclear whether this capability is influenced by tumour-initiating cells. Glioblastoma stem cells are now shown to secrete periostin, a matrix protein that recruits protumoral macrophages and enhances glioblastoma progression in mice.
10.1038/ncb3095
Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy.
Yan Kenneth,Wu Qiulian,Yan Diana H,Lee Christine H,Rahim Nasiha,Tritschler Isabel,DeVecchio Jennifer,Kalady Matthew F,Hjelmeland Anita B,Rich Jeremy N
Genes & development
Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with self-renewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1 colocalizes with CSCs in vitro and in vivo. Furthermore, Gremlin1 blocks prodifferentiation effects of BMPs, and overexpression of Gremlin1 in non-CSCs decreases their endogenous BMP signaling to promote stem-like features. Consequently, Gremlin1-overexpressing cells display increased growth and tumor formation abilities. Targeting Gremlin1 in CSCs results in impaired growth and self-renewal. Transcriptional profiling demonstrated that Gremlin1 effects were associated with inhibition of p21(WAF1/CIP1), a key CSC signaling node. This study establishes CSC-derived Gremlin1 as a driving force in maintaining glioblastoma tumor proliferation and glioblastoma hierarchies through the modulation of endogenous prodifferentiation signals.
10.1101/gad.235515.113
Active CREB1 promotes a malignant TGFβ2 autocrine loop in glioblastoma.
Rodón Laura,Gonzàlez-Juncà Alba,Inda María del Mar,Sala-Hojman Ada,Martínez-Sáez Elena,Seoane Joan
Cancer discovery
UNLABELLED:In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. SIGNIFICANCE:TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies.
10.1158/2159-8290.CD-14-0275
H3.3 Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas.
Pathania Manav,De Jay Nicolas,Maestro Nicola,Harutyunyan Ashot S,Nitarska Justyna,Pahlavan Pirasteh,Henderson Stephen,Mikael Leonie G,Richard-Londt Angela,Zhang Ying,Costa Joana R,Hébert Steven,Khazaei Sima,Ibrahim Nisreen Samir,Herrero Javier,Riccio Antonella,Albrecht Steffen,Ketteler Robin,Brandner Sebastian,Kleinman Claudia L,Jabado Nada,Salomoni Paolo
Cancer cell
Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3 and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.
10.1016/j.ccell.2017.09.014
Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation.
Nature cell biology
The tumour vascular microenvironment supports tumorigenesis not only by supplying oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feedforward mechanism in which endothelial cells (ECs), in response to tumour-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of profilin-1 (Pfn-1) at Tyr 129 in ECs induces binding to the tumour suppressor protein von Hippel-Lindau (VHL), and prevents VHL-mediated degradation of prolyl-hydroxylated HIF-1α, culminating in HIF-1α accumulation even in normoxia. Elevated HIF-1α induces expression of multiple angiogenic factors, leading to vascular abnormality and tumour progression. In a genetic model of GBM, mice with an EC-specific defect in Pfn-1 phosphorylation exhibit reduced tumour angiogenesis, normalized vasculature and improved survival. Moreover, EC-specific Pfn-1 phosphorylation is associated with tumour aggressiveness in human glioma. These findings suggest that targeting Pfn-1 phosphorylation may offer a selective strategy for therapeutic intervention of malignant solid tumours.
10.1038/ncb2954
Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells.
Schonberg David L,Miller Tyler E,Wu Qiulian,Flavahan William A,Das Nupur K,Hale James S,Hubert Christopher G,Mack Stephen C,Jarrar Awad M,Karl Robert T,Rosager Ann Mari,Nixon Anne M,Tesar Paul J,Hamerlik Petra,Kristensen Bjarne W,Horbinski Craig,Connor James R,Fox Paul L,Lathia Justin D,Rich Jeremy N
Cancer cell
Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared with tissue-specific progenitors. Direct interrogation of iron uptake demonstrated that CSCs potently extract iron from the microenvironment more effectively than other tumor cells. Systematic interrogation of iron flux determined that CSCs preferentially require transferrin receptor and ferritin, two core iron regulators, to propagate and form tumors in vivo. Depleting ferritin disrupted CSC mitotic progression, through the STAT3-FoxM1 regulatory axis, revealing an iron-regulated CSC pathway. Iron is a unique, primordial metal fundamental for earliest life forms, on which CSCs have an epigenetically programmed, targetable dependence.
10.1016/j.ccell.2015.09.002
H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo.
Silveira André B,Kasper Lawryn H,Fan Yiping,Jin Hongjian,Wu Gang,Shaw Timothy I,Zhu Xiaoyan,Larson Jon D,Easton John,Shao Ying,Yergeau Donald A,Rosencrance Celeste,Boggs Kristy,Rusch Michael C,Ding Liang,Zhang Junyuan,Finkelstein David,Noyes Rachel M,Russell Brent L,Xu Beisi,Broniscer Alberto,Wetmore Cynthia,Pounds Stanley B,Ellison David W,Zhang Jinghui,Baker Suzanne J
Acta neuropathologica
Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome. The resulting transcriptional changes recapitulate expression signatures from K27M primary DIPG tumors and are strongly enriched for genes associated with nervous system development. Integrated analysis of ChIP-seq and expression data showed that genes upregulated by the mutation are overrepresented in apparently bivalent promoters. Many of these targets are associated with more immature differentiation states. Expression profiles indicate K27M knockdown decreases proliferation and increases differentiation within lineages represented in DIPG. These data suggest that K27M-mediated loss of H3K27me3 directly regulates a subset of genes by releasing poised promoters, and contributes to tumor phenotype and growth by limiting differentiation. The delayed tumor growth associated with knockdown of H3 K27M provides evidence that this highly recurrent mutation is a relevant therapeutic target.
10.1007/s00401-019-01975-4
Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells.
Godek Kristina M,Venere Monica,Wu Quilian,Mills Kevin D,Hickey William F,Rich Jeremy N,Compton Duane A
Cancer discovery
UNLABELLED:Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TIC) that are responsible for tumorigenesis are a source of functional cellular heterogeneity, whereas chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here, we demonstrate that glioblastoma TICs display CIN with lagging chromosomes at anaphase and extensive nonclonal chromosome copy-number variations. Elevating the basal chromosome missegregation rate in TICs decreases both proliferation and the stem-like phenotype of TICs in vitro Consequently, tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors, but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold. SIGNIFICANCE:Genetic heterogeneity among TICs may produce advantageous karyotypes that lead to therapy resistance and relapse; however, we found that TICs have an upper tolerable limit for CIN. Thus, increasing the chromosome missegregation rate offers a new therapeutic strategy to eliminate TICs from tumors. Cancer Discov; 6(5); 532-45. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
10.1158/2159-8290.CD-15-1154
SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.
Science translational medicine
Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.
10.1126/scitranslmed.aaa8103
Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.
Alvarado Alvaro G,Thiagarajan Praveena S,Mulkearns-Hubert Erin E,Silver Daniel J,Hale James S,Alban Tyler J,Turaga Soumya M,Jarrar Awad,Reizes Ofer,Longworth Michelle S,Vogelbaum Michael A,Lathia Justin D
Cell stem cell
Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progress, and the mechanisms that permit this growth remain largely unknown. We report that self-renewing cancer stem cells (CSCs) in glioblastoma have low TLR4 expression that allows them to survive by disregarding inflammatory signals. Non-CSCs express high levels of TLR4 and respond to ligands. TLR4 signaling suppresses CSC properties by reducing retinoblastoma binding protein 5 (RBBP5), which is elevated in CSCs. RBBP5 activates core stem cell transcription factors, is necessary and sufficient for self-renewal, and is suppressed by TLR4 overexpression in CSCs. Our findings provide a mechanism through which CSCs persist in hostile environments because of an inability to respond to inflammatory signals.
10.1016/j.stem.2016.12.001
Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation.
Zheng Yanhua,Li Xinjian,Qian Xu,Wang Yugang,Lee Jong-Ho,Xia Yan,Hawke David H,Zhang Gang,Lyu Jianxin,Lu Zhimin
Nature cell biology
Activation of epidermal growth factor receptor (EGFR), which occurs in many types of tumour, promotes tumour progression. However, no extracellular antagonist of human EGFR has been identified. We found that human macrophage migration inhibitory factor (MIF) is O-GlcNAcylated at Ser 112/Thr 113 at its carboxy terminus. The naturally secreted and O-GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and EGF-induced EGFR activation, phosphorylation of ERK and c-Jun, cell invasion, proliferation and brain tumour formation. Activation of EGFR through mutation or its ligand binding enhances the secretion of MMP13, which degrades extracellular MIF, and results in abrogation of the negative regulation of MIF on EGFR. The finding that EGFR activation downregulates its antagonist in the tumour microenvironment represents an important feedforward mechanism for human tumour cells to enhance EGFR signalling and promote tumorigenesis.
10.1038/ncb3222
H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers.
Fang Dong,Gan Haiyun,Cheng Liang,Lee Jeong-Heon,Zhou Hui,Sarkaria Jann N,Daniels David J,Zhang Zhiguo
eLife
Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.
10.7554/eLife.36696
IDH1 Mutation Promotes Tumorigenesis by Inhibiting JNK Activation and Apoptosis Induced by Serum Starvation.
Jiang Bin,Zhang Jia,Xia Jinmei,Zhao Wentao,Wu Yanan,Shi Minggang,Luo Lianzhong,Zhou Huamin,Chen Ai,Ma Huanhuan,Zhao Qingwen,Suleman Muhammad,Lin Furong,Zhou Lin,Wang Jinyang,Zhang Yan,He Ying,Li Xiaotong,Hung Li-Man,Mak Tak Wah,Li Qinxi
Cell reports
Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis. We show here, using IDH1-R132Q knockin mutant mouse cells, that 2-HG inhibits JNK activation induced only by SS and not by UV or doxorubicin, and thus can block apoptosis. Upon SS, Cdc42 normally disrupts mixed lineage kinase 3's (MLK3's) auto-inhibition, triggering the MLK3-MKK4/7-JNK-Bim apoptotic cascade. 2-HG binds to Cdc42 and abolishes its association with MLK3, inactivating MLK3 and apoptosis. Allograft tumor assays in mice demonstrate that this mechanism contributes to tumorigenesis driven by mutant IDH1, a result confirmed by detection of JNK inactivation in human gliomas harboring IDH1-R132H mutations.
10.1016/j.celrep.2017.03.053
Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth.
Pietras Alexander,Katz Amanda M,Ekström Elin J,Wee Boyoung,Halliday John J,Pitter Kenneth L,Werbeck Jillian L,Amankulor Nduka M,Huse Jason T,Holland Eric C
Cell stem cell
Stem-like glioma cells reside within a perivascular niche and display hallmark radiation resistance. An understanding of the mechanisms underlying these properties will be vital for the development of effective therapies. Here, we show that the stem cell marker CD44 promotes cancer stem cell phenotypes and radiation resistance. In a mouse model of glioma, Cd44(-/-) and Cd44(+/-) animals showed improved survival compared to controls. The CD44 ligand osteopontin shared a perivascular expression pattern with CD44 and promoted glioma stem cell-like phenotypes. These effects were mediated via the γ-secretase-regulated intracellular domain of CD44, which promoted aggressive glioma growth in vivo and stem cell-like phenotypes via CBP/p300-dependent enhancement of HIF-2α activity. In human glioblastoma multiforme, expression of CD44 correlated with hypoxia-induced gene signatures and poor survival. Altogether, these data suggest that in the glioma perivascular niche, osteopontin promotes stem cell-like properties and radiation resistance in adjacent tumor cells via activation of CD44 signaling.
10.1016/j.stem.2014.01.005
Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts.
Bejarano Leire,Schuhmacher Alberto J,Méndez Marinela,Megías Diego,Blanco-Aparicio Carmen,Martínez Sonia,Pastor Joaquín,Squatrito Massimo,Blasco Maria A
Cancer cell
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.
10.1016/j.ccell.2017.10.006
Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma.
Breunig Joshua J,Levy Rachelle,Antonuk C Danielle,Molina Jessica,Dutra-Clarke Marina,Park Hannah,Akhtar Aslam Abbasi,Kim Gi Bum,Hu Xin,Bannykh Serguei I,Verhaak Roel G W,Danielpour Moise
Cell reports
As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.
10.1016/j.celrep.2015.06.012
BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation.
Cancer cell
Adhesion G protein-coupled receptors (ADGRs) encompass 33 human transmembrane proteins with long N termini involved in cell-cell and cell-matrix interactions. We show the ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in medulloblastomas (MBs) through a methyl-CpG binding protein MBD2-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors, and leads to accelerated tumor growth in the Ptch1 transgenic MB mouse model. BAI1 prevents Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. Reactivation of BAI1/p53 signaling axis by a brain-permeable MBD2 pathway inhibitor suppresses MB growth in vivo. Altogether, our data define BAI1's physiological role in tumorigenesis and directly couple an ADGR to cancer formation.
10.1016/j.ccell.2018.05.006
Driving glioblastoma growth by alternative polyadenylation.
Han Ting,Kim John K
Cell research
Global shortening of 3' untranslated regions (3' UTRs) through alternative polyadenylation is an emerging hallmark of cancer. A recent study identifies the cleavage factor Im 25 (CFIm25) as an important mediator of 3' UTR shortening in glioblastomas and demonstrates a causal relationship between alternative polyadenylation and cancer cell proliferation.
10.1038/cr.2014.88
5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.
Acta neuropathologica
Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.
10.1007/s00401-018-1821-3
Functional genomics analyses of RNA-binding proteins reveal the splicing regulator SNRPB as an oncogenic candidate in glioblastoma.
Genome biology
BACKGROUND:Glioblastoma (GBM) is the most common and aggressive type of brain tumor. Currently, GBM has an extremely poor outcome and there is no effective treatment. In this context, genomic and transcriptomic analyses have become important tools to identify new avenues for therapies. RNA-binding proteins (RBPs) are master regulators of co- and post-transcriptional events; however, their role in GBM remains poorly understood. To further our knowledge of novel regulatory pathways that could contribute to gliomagenesis, we have conducted a systematic study of RBPs in GBM. RESULTS:By measuring expression levels of 1542 human RBPs in GBM samples and glioma stem cell samples, we identified 58 consistently upregulated RBPs. Survival analysis revealed that increased expression of 21 RBPs was also associated with a poor prognosis. To assess the functional impact of those RBPs, we modulated their expression in GBM cell lines and performed viability, proliferation, and apoptosis assays. Combined results revealed a prominent oncogenic candidate, SNRPB, which encodes core spliceosome machinery components. To reveal the impact of SNRPB on splicing and gene expression, we performed its knockdown in a GBM cell line followed by RNA sequencing. We found that the affected genes were involved in RNA processing, DNA repair, and chromatin remodeling. Additionally, genes and pathways already associated with gliomagenesis, as well as a set of general cancer genes, also presented with splicing and expression alterations. CONCLUSIONS:Our study provides new insights into how RBPs, and specifically SNRPB, regulate gene expression and directly impact GBM development.
10.1186/s13059-016-0990-4
Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma.
Lee Chul-Hwan,Yu Jia-Ray,Granat Jeffrey,Saldaña-Meyer Ricardo,Andrade Joshua,LeRoy Gary,Jin Ying,Lund Peder,Stafford James M,Garcia Benjamin A,Ueberheide Beatrix,Reinberg Danny
Genes & development
The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.
10.1101/gad.328773.119
A BCL6/BCOR/SIRT1 complex triggers neurogenesis and suppresses medulloblastoma by repressing Sonic Hedgehog signaling.
Tiberi Luca,Bonnefont Jérôme,van den Ameele Jelle,Le Bon Serge-Daniel,Herpoel Adèle,Bilheu Angéline,Baron Beverly W,Vanderhaeghen Pierre
Cancer cell
Disrupted differentiation during development can lead to oncogenesis, but the underlying mechanisms remain poorly understood. Here we identify BCL6, a transcriptional repressor and lymphoma oncoprotein, as a pivotal factor required for neurogenesis and tumor suppression of medulloblastoma (MB). BCL6 is necessary for and capable of preventing the development of GNP-derived MB in mice, and can block the growth of human MB cells in vitro. BCL6 neurogenic and oncosuppressor effects rely on direct transcriptional repression of Gli1 and Gli2 effectors of the SHH pathway, through recruitment of BCOR corepressor and SIRT1 deacetylase. Our findings identify the BCL6/BCOR/SIRT1 complex as a potent repressor of the SHH pathway in normal and oncogenic neural development, with direct diagnostic and/or therapeutic relevance for SHH MB.
10.1016/j.ccell.2014.10.021
The dystroglycan receptor maintains glioma stem cells in the vascular niche.
Acta neuropathologica
Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.
10.1007/s00401-019-02069-x
Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT.
Acta neuropathologica
The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.
10.1007/s00401-017-1690-1
A CREB1-TGFβ2 self-sustaining loop in glioblastoma.
Wotton David
Cancer discovery
A subset of glioblastomas (GBM) has high levels of TGFβ signaling, and anti-TGFβ therapies are being pursued as treatments for GBM. The work presented here identifies CREB1 as a potential biomarker for TGFβ-dependent GBM. CREB1 integrates signaling from TGFβ and the PI3K pathway and nucleates a self-sustaining signaling loop that maintains TGFβ2 expression in GBM with high CREB1 levels.
10.1158/2159-8290.CD-14-0861
Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells.
Kupp Robert,Shtayer Lior,Tien An-Chi,Szeto Emily,Sanai Nader,Rowitch David H,Mehta Shwetal
Cell reports
The basic helix-loop-helix (bHLH) transcription factor OLIG2 is a master regulator of oligodendroglial fate decisions and tumorigenic competence of glioma stem-like cells (GSCs). However, the molecular mechanisms underlying dysregulation of OLIG2 function during gliomagenesis remains poorly understood. Here, we show that OLIG2 modulates growth factor signaling in two distinct populations of GSCs, characterized by expression of either the epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRα). Biochemical analyses of OLIG2 function in normal and malignant neural progenitors reveal a positive feedforward loop between OLIG2 and EGFR to sustain co-expression. Furthermore, loss of OLIG2 function results in mesenchymal transformation in PDGFRα(HIGH) GSCs, a phenomenon that appears to be circumscribed in EGFR(HIGH) GSCs. Exploitation of OLIG2's dual and antithetical, pro-mitotic (EGFR-driven), and lineage-specifying (PDGFRα-driven) functions by glioma cells appears to be critical for sustaining growth factor signaling and GSC molecular subtype.
10.1016/j.celrep.2016.08.040
expression promotes resistance to alkylating chemotherapy in gliomas.
Wu Longtao,Bernal Giovanna M,Cahill Kirk E,Pytel Peter,Fitzpatrick Carrie A,Mashek Heather,Weichselbaum Ralph R,Yamini Bakhtiar
Science translational medicine
The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated -methylguanine DNA methyltransferase () promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.
10.1126/scitranslmed.aar2238
Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.
Sarkar Susobhan,Döring Axinia,Zemp Franz J,Silva Claudia,Lun Xueqing,Wang Xiuling,Kelly John,Hader Walter,Hamilton Mark,Mercier Philippe,Dunn Jeff F,Kinniburgh Dave,van Rooijen Nico,Robbins Stephen,Forsyth Peter,Cairncross Gregory,Weiss Samuel,Yong V Wee
Nature neuroscience
Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.
10.1038/nn.3597
A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2.
Zhou Jing,Tien An-Chi,Alberta John A,Ficarro Scott B,Griveau Amelie,Sun Yu,Deshpande Janhavee S,Card Joseph D,Morgan-Smith Meghan,Michowski Wojciech,Hashizume Rintaro,James C David,Ligon Keith L,Snider William D,Sicinski Peter,Marto Jarrod A,Rowitch David H,Stiles Charles D
Cell reports
During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3α/β [GSK3α/β], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged "acid blob" in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics.
10.1016/j.celrep.2017.03.003
Cortical GABAergic excitation contributes to epileptic activities around human glioma.
Pallud Johan,Le Van Quyen Michel,Bielle Franck,Pellegrino Christophe,Varlet Pascale,Cresto Noemie,Baulac Michel,Duyckaerts Charles,Kourdougli Nazim,Chazal Geneviève,Devaux Bertrand,Rivera Claudio,Miles Richard,Capelle Laurent,Huberfeld Gilles
Science translational medicine
Brain gliomas are highly epileptogenic. Excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glioma cells. Thus, the contribution of γ-aminobutyric acidergic (GABAergic) mechanisms that depend on intracellular chloride merits closer study. We studied the occurrence, networks, cells, and signaling basis of epileptic activities in neocortical slices from the peritumoral surgical margin resected around human brain gliomas. Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges, synchronized, with a high-frequency oscillation signature, in superficial layers of neocortex around areas of glioma infiltration. Interictal-like events depended both on glutamatergic AMPA receptor-mediated transmission and on depolarizing GABAergic signaling. GABA released by interneurons depolarized 65% of pyramidal cells, in which chloride homeostasis was perturbed because of changes in expression of neuronal chloride cotransporters: KCC2 (K-Cl cotransporter 2) was reduced by 42% and expression of NKCC1 (Na-K-2Cl cotransporter 1) increased by 144%. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. This study shows that epileptic activities are sustained by excitatory effects of GABA in human peritumoral neocortex, as reported in temporal lobe epilepsies, suggesting that both glutamate and GABA signaling and cellular chloride regulation processes, all also involved in oncogenesis as already shown, induce an imbalance between synaptic excitation and inhibition underlying epileptic discharges in glioma patients. Thus, the control of chloride in neurons and glioma cells may provide a therapeutic target for patients with epileptogenic gliomas.
10.1126/scitranslmed.3008065
The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma.
Venere Monica,Horbinski Craig,Crish James F,Jin Xun,Vasanji Amit,Major Jennifer,Burrows Amy C,Chang Cathleen,Prokop John,Wu Quilian,Sims Peter A,Canoll Peter,Summers Matthew K,Rosenfeld Steven S,Rich Jeremy N
Science translational medicine
The proliferative and invasive nature of malignant cancers drives lethality. In glioblastoma, these two processes are presumed mutually exclusive and hence termed "go or grow." We identified a molecular target that shuttles between these disparate cellular processes-the molecular motor KIF11. Inhibition of KIF11 with a highly specific small-molecule inhibitor stopped the growth of the more treatment-resistant glioblastoma tumor-initiating cells (TICs, or cancer stem cells) as well as non-TICs and impeded tumor initiation and self-renewal of the TIC population. Targeting KIF11 also hit the other arm of the "go or grow" cell fate decision by reducing glioma cell invasion. Administration of a KIF11 inhibitor to mice bearing orthotopic glioblastoma prolonged their survival. In its role as a shared molecular regulator of cell growth and motility across intratumoral heterogeneity, KIF11 is a compelling therapeutic target for glioblastoma.
10.1126/scitranslmed.aac6762
Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma.
Lu Fanghui,Chen Ying,Zhao Chuntao,Wang Haibo,He Danyang,Xu Lingli,Wang Jincheng,He Xuelian,Deng Yaqi,Lu Ellen E,Liu Xue,Verma Ravinder,Bu Hong,Drissi Rachid,Fouladi Maryam,Stemmer-Rachamimov Anat O,Burns Dennis,Xin Mei,Rubin Joshua B,Bahassi El Mustapha,Canoll Peter,Holland Eric C,Lu Q Richard
Cancer cell
Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs.
10.1016/j.ccell.2016.03.027
CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells.
Mukherjee Subhas,Tucker-Burden Carol,Kaissi Emily,Newsam Austin,Duggireddy Hithardhi,Chau Monica,Zhang Changming,Diwedi Bhakti,Rupji Manali,Seby Sandra,Kowalski Jeanne,Kong Jun,Read Renee,Brat Daniel J
Cell reports
Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP. Finally, our TCGA GBM data analysis revealed that CDK5, stem cell, and asymmetric cell division markers segregate within non-mesenchymal patient clusters, which may indicate preferential dependence on CDK5 signaling and sensitivity to its inhibition in this group.
10.1016/j.celrep.2018.04.016
Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation.
Minata Mutsuko,Audia Alessandra,Shi Junfeng,Lu Songjian,Bernstock Joshua,Pavlyukov Marat S,Das Arvid,Kim Sung-Hak,Shin Yong Jae,Lee Yeri,Koo Harim,Snigdha Kirti,Waghmare Indrayani,Guo Xing,Mohyeldin Ahmed,Gallego-Perez Daniel,Wang Jia,Chen Dongquan,Cheng Peng,Mukheef Farah,Contreras Minerva,Reyes Joel F,Vaillant Brian,Sulman Erik P,Cheng Shi-Yuan,Markert James M,Tannous Bakhos A,Lu Xinghua,Kango-Singh Madhuri,Lee L James,Nam Do-Hyun,Nakano Ichiro,Bhat Krishna P
Cell reports
Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133 PN signature, transition to a CD109 MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133/CD109 cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.
10.1016/j.celrep.2019.01.076
Hematogenous dissemination of glioblastoma multiforme.
Müller Carolin,Holtschmidt Johannes,Auer Martina,Heitzer Ellen,Lamszus Katrin,Schulte Alexander,Matschke Jakob,Langer-Freitag Sabine,Gasch Christin,Stoupiec Malgorzata,Mauermann Oliver,Peine Sven,Glatzel Markus,Speicher Michael R,Geigl Jochen B,Westphal Manfred,Pantel Klaus,Riethdorf Sabine
Science translational medicine
Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor in adults. The dogma that GBM spread is restricted to the brain was challenged by reports on extracranial metastases after organ transplantation from GBM donors. We identified circulating tumor cells (CTCs) in peripheral blood (PB) from 29 of 141 (20.6%) GBM patients by immunostaining of enriched mononuclear cells with antibodies directed against glial fibrillary acidic protein (GFAP). Tumor cell spread was not significantly enhanced by surgical intervention. The tumor nature of GFAP-positive cells was supported by the absence of those cells in healthy volunteers and the presence of tumor-specific aberrations such as EGFR gene amplification and gains and losses in genomic regions of chromosomes 7 and 10. Release of CTCs was associated with EGFR gene amplification, suggesting a growth potential of these cells. We demonstrate that hematogenous GBM spread is an intrinsic feature of GBM biology.
10.1126/scitranslmed.3009095
Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State.
Nagaraja Surya,Quezada Michael A,Gillespie Shawn M,Arzt Marlene,Lennon James J,Woo Pamelyn J,Hovestadt Volker,Kambhampati Madhuri,Filbin Mariella G,Suva Mario L,Nazarian Javad,Monje Michelle
Molecular cell
Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG.
10.1016/j.molcel.2019.08.030
Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.
Nature cell biology
Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.
10.1038/ncb3429
A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.
Fan QiWen,Aksoy Ozlem,Wong Robyn A,Ilkhanizadeh Shirin,Novotny Chris J,Gustafson William C,Truong Albert Yi-Que,Cayanan Geraldine,Simonds Erin F,Haas-Kogan Daphne,Phillips Joanna J,Nicolaides Theodore,Okaniwa Masanori,Shokat Kevan M,Weiss William A
Cancer cell
Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1.
10.1016/j.ccell.2017.01.014
The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13.
Hu Yan,Zhang Meilian,Tian Ningyu,Li Dengke,Wu Fan,Hu Peishan,Wang Zhixing,Wang Liping,Hao Wei,Kang Jingting,Yin Bin,Zheng Zhi,Jiang Tao,Yuan Jiangang,Qiang Boqin,Han Wei,Peng Xiaozhong
The Journal of clinical investigation
Gliomas account for approximately 80% of primary malignant tumors in the central nervous system. Despite aggressive therapy, the prognosis of patients remains extremely poor. Glioma stem cells (GSCs) which considered as the potential target of therapy for their crucial role in therapeutic resistance and tumor recurrence, are believed to be key factors for the disappointing outcome. Here, we took advantage of GSCs as the cell model to perform high-throughput drug screening and the old antibiotic, clofoctol, was identified as the most effective compound, showing reduction of colony-formation and induction of apoptosis of GSCs. Moreover, growth of tumors was inhibited obviously in vivo after clofoctol treatment especially in primary patient-derived xenografts (PDXs) and transgenic xenografts. The anticancer mechanisms demonstrated by analyzing related downstream genes and discovering the targeted binding protein revealed that clofoctol exhibited the inhibition of GSCs by upregulation of Kruppel-like factor 13 (KLF13), a tumor suppressor gene, through clofoctol's targeted binding protein, Upstream of N-ras (UNR). Collectively, these data demonstrated that induction of KLF13 expression suppressed growth of gliomas and provided a potential therapy for gliomas targeting GSCs. Importantly, our results also identified the RNA-binding protein UNR as a drug target.
10.1172/JCI124979
Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration.
Prahl Louis S,Bangasser Patrick F,Stopfer Lauren E,Hemmat Mahya,White Forest M,Rosenfeld Steven S,Odde David J
Cell reports
Microtubule-targeting agents (MTAs) are widely used chemotherapy drugs capable of disrupting microtubule-dependent cellular functions, such as division and migration. We show that two clinically approved MTAs, paclitaxel and vinblastine, each suppress stiffness-sensitive migration and polarization characteristic of human glioma cells on compliant hydrogels. MTAs influence microtubule dynamics and cell traction forces by nearly opposite mechanisms, the latter of which can be explained by a combination of changes in myosin motor and adhesion clutch number. Our results support a microtubule-dependent signaling-based model for controlling traction forces through a motor-clutch mechanism, rather than microtubules directly relieving tension within F-actin and adhesions. Computational simulations of cell migration suggest that increasing protrusion number also impairs stiffness-sensitive migration, consistent with experimental MTA effects. These results provide a theoretical basis for the role of microtubules and mechanisms of MTAs in controlling cell migration.
10.1016/j.celrep.2018.10.101
Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21.
Abels Erik R,Maas Sybren L N,Nieland Lisa,Wei Zhiyun,Cheah Pike See,Tai Eric,Kolsteeg Christy-Joy,Dusoswa Sophie A,Ting David T,Hickman Suzanne,El Khoury Joseph,Krichevsky Anna M,Broekman Marike L D,Breakefield Xandra O
Cell reports
Gliomas are primary, diffusely infiltrating brain tumors. Microglia are innate immune cells in the CNS and make up a substantial portion of the tumor mass. Glioma cells shape their microenvironment, communicating with and reprogramming surrounding cells, resulting in enhanced angiogenesis, immune suppression, and remodeling of the extracellular matrix. Glioma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Mouse glioma cells stably expressing a palmitoylated GFP to label EVs were implanted intracranially into syngeneic miR-21-null mice. Here, we demonstrate functional delivery of miR-21, regulating specific downstream mRNA targets in microglia after uptake of tumor-derived EVs. These findings attest to EV-dependent microRNA delivery as studied in an in vivo-based model and provide insight into the reprograming of microglial cells by tumor cells to create a favorable microenvironment for cancer progression.
10.1016/j.celrep.2019.08.036
Messenger RNA Methylation Regulates Glioblastoma Tumorigenesis.
Dixit Deobrat,Xie Qi,Rich Jeremy N,Zhao Jing Crystal
Cancer cell
Messenger RNA (mRNA) modification provides an additional layer of gene regulation in cells. In this issue of Cancer Cell, Zhang et al. report that ALKBH5, a demethylase of the mRNA modification N-methyladenosine, regulates proliferation and self-renewal of glioblastoma stem-like cells by modulating pre-mRNA stability and expression of the FOXM1 gene.
10.1016/j.ccell.2017.03.010
Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma.
Acta neuropathologica
Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas database and comparing the results with those of 173 S-GBM cases. We found that M-GBMs had no IDH1, ATRX, or PDGFRA mutations and were significantly associated with the mesenchymal subtype. We also identified the CYB5R2 gene to be hypo-methylated and overexpressed in M-GBMs. The expression level of CYB5R2 was significantly associated with patient survival in two major independent GBM cohorts, totaling 758 cases. The IDH1 mutation was markedly associated with CYB5R2 promoter methylation, but the survival influence of CYB5R2 was independent of IDH1 mutation status. CYB5R2 expression was significantly associated with collagen maturation and the catabolic process and immunoregulation pathways. These results reveal that M-GBMs have some underlying genetic and epigenetic characteristics that are associated with poor prognosis and that CYB5R2 is a new epigenetic marker for GBM prognosis.
10.1007/s00401-015-1470-8
Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype.
Nature immunology
Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.
10.1038/ni.3545
Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells.
Man Jianghong,Yu Xingjiang,Huang Haidong,Zhou Wenchao,Xiang Chaomei,Huang Haohao,Miele Lucio,Liu Zhenggang,Bebek Gurkan,Bao Shideng,Yu Jennifer S
Cell stem cell
Tumor hypoxia is associated with poor patient survival and is a characteristic of glioblastoma. Notch signaling is implicated in maintaining glioma stem-like cells (GSCs) within the hypoxic niche, although the molecular mechanisms linking hypoxia to Notch activation have not been clearly delineated. Here we show that Vasorin is a critical link between hypoxia and Notch signaling in GSCs. Vasorin is preferentially induced in GSCs by a HIF1α/STAT3 co-activator complex and stabilizes Notch1 protein at the cell membrane. This interaction prevents Numb from binding Notch1, rescuing it from Numb-mediated lysosomal degradation. Thus, Vasorin acts as a switch to augment Notch signaling under hypoxic conditions. Vasorin promotes tumor growth and reduces survival in mouse models of glioblastoma, and its expression correlates with increased aggression of human gliomas. These findings provide mechanistic insights into how hypoxia promotes Notch signaling in glioma and identify Vasorin as a potential therapeutic target.
10.1016/j.stem.2017.10.005
A Cell-Surface Membrane Protein Signature for Glioblastoma.
Ghosh Dhimankrishna,Funk Cory C,Caballero Juan,Shah Nameeta,Rouleau Katherine,Earls John C,Soroceanu Liliana,Foltz Greg,Cobbs Charles S,Price Nathan D,Hood Leroy
Cell systems
We present a systems strategy that facilitated the development of a molecular signature for glioblastoma (GBM), composed of 33 cell-surface transmembrane proteins. This molecular signature, GBMSig, was developed through the integration of cell-surface proteomics and transcriptomics from patient tumors in the REMBRANDT (n = 228) and TCGA datasets (n = 547) and can separate GBM patients from control individuals with a Matthew's correlation coefficient value of 0.87 in a lock-down test. Functionally, 17/33 GBMSig proteins are associated with transforming growth factor β signaling pathways, including CD47, SLC16A1, HMOX1, and MRC2. Knockdown of these genes impaired GBM invasion, reflecting their role in disease-perturbed changes in GBM. ELISA assays for a subset of GBMSig (CD44, VCAM1, HMOX1, and BIGH3) on 84 plasma specimens from multiple clinical sites revealed a high degree of separation of GBM patients from healthy control individuals (area under the curve is 0.98 in receiver operating characteristic). In addition, a classifier based on these four proteins differentiated the blood of pre- and post-tumor resections, demonstrating potential clinical value as biomarkers.
10.1016/j.cels.2017.03.004
Expression of lncRNAs in Low-Grade Gliomas and Glioblastoma Multiforme: An In Silico Analysis.
PLoS medicine
BACKGROUND:Each year, over 16,000 patients die from malignant brain cancer in the US. Long noncoding RNAs (lncRNAs) have recently been shown to play critical roles in regulating neurogenesis and brain tumor progression. To better understand the role of lncRNAs in brain cancer, we performed a global analysis to identify and characterize all annotated and novel lncRNAs in both grade II and III gliomas as well as grade IV glioblastomas (glioblastoma multiforme [GBM]). METHODS AND FINDINGS:We determined the expression of all lncRNAs in over 650 brain cancer and 70 normal brain tissue RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and other publicly available datasets. We identified 611 induced and 677 repressed lncRNAs in glial tumors relative to normal brains. Hundreds of lncRNAs were specifically expressed in each of the three lower grade glioma (LGG) subtypes (IDH1/2 wt, IDH1/2 mut, and IDH1/2 mut 1p19q codeletion) and the four subtypes of GBMs (classical, mesenchymal, neural, and proneural). Overlap between the subtype-specific lncRNAs in GBMs and LGGs demonstrated similarities between mesenchymal GBMs and IDH1/2 wt LGGs, with 2-fold higher overlap than would be expected by random chance. Using a multivariate Cox regression survival model, we identified 584 and 282 lncRNAs that were associated with a poor and good prognosis, respectively, in GBM patients. We developed a survival algorithm for LGGs based on the expression of 64 lncRNAs that was associated with patient prognosis in a test set (hazard ratio [HR] = 2.168, 95% CI = 1.765-2.807, p < 0.001) and validation set (HR = 1.921, 95% CI = 1.333-2.767, p < 0.001) of patients from TCGA. The main limitations of this study are that further work is needed to investigate the clinical relevance of our findings, and that validation in an independent dataset is needed to determine the robustness of our survival algorithm. CONCLUSIONS:This work identifies a panel of lncRNAs that appear to be prognostic in gliomas and provides a critical resource for future studies examining the role of lncRNAs in brain cancers.
10.1371/journal.pmed.1002192
Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma.
Nature reviews. Cancer
As tumours evolve, the daughter cells of the initiating cell often become molecularly heterogeneous and develop different functional properties and therapeutic vulnerabilities. In glioblastoma (GBM), a lethal form of brain cancer, the heterogeneous expression of the epidermal growth factor receptor (EGFR) poses a substantial challenge for the effective use of EGFR-targeted therapies. Understanding the mechanisms that cause EGFR heterogeneity in GBM should provide better insights into how they, and possibly other amplified receptor tyrosine kinases, affect cellular signalling, metabolism and drug resistance.
10.1038/nrc3918
Epigenetic Control of Fatty-Acid Metabolism Sustains Glioma Stem Cells.
Affronti Hayley C,Wellen Kathryn E
Cancer discovery
In this issue of , Gimple and colleagues examine superenhancers in glioblastoma and glioma stem cells (GSC), identifying one which promotes expression of ELOVL2, an enzyme in polyunsaturated fatty acid (PUFA) synthesis. They find that ELOVL2 products help maintain cell membrane organization and EGFR signaling in GSCs, and that targeting PUFA metabolism along with EGFR offers a potential novel therapeutic strategy for glioblastoma..
10.1158/2159-8290.CD-19-0733
CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells.
Johansson Elinn,Grassi Elisa S,Pantazopoulou Vasiliki,Tong Bei,Lindgren David,Berg Tracy J,Pietras Elin J,Axelson Håkan,Pietras Alexander
Cell reports
Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen.
10.1016/j.celrep.2017.07.049
Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma.
Ranjit Melissa,Hirano Masaki,Aoki Kosuke,Okuno Yusuke,Ohka Fumiharu,Yamamichi Akane,Kato Akira,Maeda Sachi,Motomura Kazuya,Matsuo Keitaro,Enomoto Atsushi,Ino Yasushi,Todo Tomoki,Takahashi Masahide,Wakabayashi Toshihiko,Kato Takuya,Natsume Atsushi
Cell reports
RET finger protein (RFP) forms a complex with histone deacetylase 1, resulting in aberrant deacetylation of H3K27ac and dysregulation of cis-regulatory elements. We evaluated the modulatory effects of RFP knockdown on cis-regulatory elements, gene expression, and chemosensitivity to temozolomide both in glioblastoma cells and in an intracranial glioblastoma model. The combination of RFP knockdown and temozolomide treatment markedly suppressed the glioblastoma cell growth due to oxidative stress and aberrant cell cycle and increased survival time in mice with glioblastoma. ChIP-seq and RNA-seq revealed that RFP knockdown increased or decreased activity of numerous cis-regulatory elements that lie adjacent to genes that control functions such as apoptosis, mitosis, DNA replication, and cell cycle: FOXO1, TBP2, and PARPBP. This study suggests that RFP contributes to chemoresistance via aberrant deacetylation of histone H3 at K27, whereas dysregulation of RFP-associated cis-regulatory elements in glioma and RFP knockdown combined with temozolomide is an effective treatment strategy for lethal glioma.
10.1016/j.celrep.2019.01.109
Distinct molecular profile of diffuse cerebellar gliomas.
Acta neuropathologica
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.
10.1007/s00401-017-1771-1
Cell of origin for malignant gliomas and its implication in therapeutic development.
Zong Hui,Parada Luis F,Baker Suzanne J
Cold Spring Harbor perspectives in biology
Malignant glioma remains incurable despite tremendous advancement in basic research and clinical practice. The identification of the cell(s) of origin should provide deep insights into leverage points for one to halt disease progression. Here we summarize recent studies that support the notion that neural stem cell (NSC), astrocyte, and oligodendrocyte precursor cell (OPC) can all serve as the cell of origin. We also lay out important considerations on technical rigor for further exploring this subject. Finally, we share perspectives on how one could apply the knowledge of cell of origin to develop effective treatment methods. Although it will be a difficult battle, victory should be within reach as along as we continue to assimilate new information and facilitate the collaboration among basic scientists, translational researchers, and clinicians.
10.1101/cshperspect.a020610
GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients.
eLife
GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent from the capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in the capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We use NanoSIMS imaging to show that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.
10.7554/eLife.47178
Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma.
Akgül Seçkin,Li Yinghua,Zheng Siyuan,Kool Marcel,Treisman Daniel M,Li Chaoyang,Wang Yuan,Gröbner Susanne,Ikenoue Tsuneo,Shen Yiping,Camelo-Piragua Sandra,Tomasek Gerald,Stark Sebastian,Guduguntla Vinay,Gusella James F,Guan Kun-Liang,Pfister Stefan M,Verhaak Roel G W,Zhu Yuan
Cell reports
Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.
10.1016/j.celrep.2018.06.050
Physical and Molecular Landscapes of Mouse Glioma Extracellular Vesicles Define Heterogeneity.
Cell reports
Cancer extracellular vesicles (EVs) are highly heterogeneous, which impedes our understanding of their function as intercellular communication agents and biomarkers. To deconstruct this heterogeneity, we analyzed extracellular RNAs (exRNAs) and extracellular proteins (exPTNs) from size fractionation of large, medium, and small EVs and ribonucleoprotein complexes (RNPs) from mouse glioblastoma cells by RNA sequencing and quantitative proteomics. mRNA from medium-sized EVs most closely reflects the cellular transcriptome, whereas small EV exRNA is enriched in small non-coding RNAs and RNPs contain precisely processed tRNA fragments. The exPTN composition of EVs and RNPs reveals that they are closely related by vesicle type, independent of their cellular origin, and single EV analysis reveals that small EVs are less heterogeneous in their protein content than larger ones. We provide a foundation for better understanding of segregation of macromolecules in glioma EVs through a catalog of diverse exRNAs and exPTNs.
10.1016/j.celrep.2019.05.089
Environmental stimuli shape microglial plasticity in glioma.
Garofalo Stefano,Porzia Alessandra,Mainiero Fabrizio,Di Angelantonio Silvia,Cortese Barbara,Basilico Bernadette,Pagani Francesca,Cignitti Giorgio,Chece Giuseppina,Maggio Roberta,Tremblay Marie-Eve,Savage Julie,Bisht Kanchan,Esposito Vincenzo,Bernardini Giovanni,Seyfried Thomas,Mieczkowski Jakub,Stepniak Karolina,Kaminska Bozena,Santoni Angela,Limatola Cristina
eLife
In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-γ produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-γ, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.
10.7554/eLife.33415
GABPβ1L Wakes Up TERT.
Rahme Gilbert J,Gaskell Elizabeth,Bernstein Bradley E
Cancer cell
TERT catalyzes telomere maintenance. While silenced in most normal somatic cells, TERT is expressed in cancer, often due to promoter mutations, facilitating replicative immortality. In this issue of Cancer Cell, Mancini et al. demonstrate that GABPβ1L is required for mutant TERT promoter activity, thus identifying a potential therapeutic target.
10.1016/j.ccell.2018.08.011
Autophagy and oxidative stress in gliomas with IDH1 mutations.
Gilbert Misty R,Liu Yinxing,Neltner Janna,Pu Hong,Morris Andrew,Sunkara Manjula,Pittman Thomas,Kyprianou Natasha,Horbinski Craig
Acta neuropathologica
IDH1 mutations in gliomas associate with longer survival. Prooxidant and antiproliferative effects of IDH1 mutations and its D-2-hydroxyglutarate (2-HG) product have been described in vitro, but inconsistently observed. It is also unclear whether overexpression of mutant IDH1 in wild-type cells accurately phenocopies the effects of endogenous IDH1-mutations on tumor apoptosis and autophagy. Herein we investigated the effects of 2-HG and mutant IDH1 overexpression on proliferation, apoptosis, oxidative stress, and autophagy in IDH1 wild-type glioma cells, and compared those results with patient-derived tumors. 2-HG reduced viability and proliferation of U87MG and LN18 cells, triggered apoptosis in LN18 cells, and autophagy in U87MG cells. In vitro studies and flank xenografts of U87MG cells overexpressing R132H IDH1 exhibited increased oxidative stress, including increases of both manganese superoxide dismutase (MnSOD) and p62. Patient-derived IDH1-mutant tumors showed no significant differences in apoptosis or autophagy, but showed p62 accumulation and actually trended toward reduced MnSOD expression. These data indicate that mutant IDH1 and 2-HG can induce oxidative stress, autophagy, and apoptosis, but these effects vary greatly according to cell type.
10.1007/s00401-013-1194-6
Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma.
Haas Tobias L,Sciuto Maria Rita,Brunetto Lidia,Valvo Cecilia,Signore Michele,Fiori Micol E,di Martino Simona,Giannetti Stefano,Morgante Liliana,Boe Alessandra,Patrizii Michele,Warnken Uwe,Schnölzer Martina,Ciolfi Andrea,Di Stefano Chiara,Biffoni Mauro,Ricci-Vitiani Lucia,Pallini Roberto,De Maria Ruggero
Cell stem cell
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.
10.1016/j.stem.2017.04.009
FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas.
Brand Frank,Förster Alisa,Christians Anne,Bucher Martin,Thomé Carina M,Raab Marc S,Westphal Manfred,Pietsch Torsten,von Deimling Andreas,Reifenberger Guido,Claus Peter,Hentschel Bettina,Weller Michael,Weber Ruthild G
Acta neuropathologica
In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.
10.1007/s00401-019-02067-z
T Cell Exhaustion in Glioblastoma: Intricacies of Immune Checkpoints.
Mirzaei Reza,Sarkar Susobhan,Yong V Wee
Trends in immunology
Glioblastoma is an aggressive and incurable primary brain tumor. While the blockade of immune checkpoints leads to reversal of T cell exhaustion in many cancers, the efficacy of this therapy in glioblastoma requires further consideration of the brain microenvironment beyond T cell activity. Neural cells are crucially dependent on glucose for survival, and tumor cells rabidly consume glucose; the glucose-deprived microenvironment further elevates immune checkpoint molecules to benefit tumor growth and exacerbate T cell exhaustion. We review here how immune checkpoints drive exhaustion in T cells while favoring tumor metabolism, and discuss how glucose competition in the unique CNS milieu is an important consideration to improve the outcomes of immune checkpoint blockade in glioblastoma.
10.1016/j.it.2016.11.005
DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis.
Yin Jinlong,Park Gunwoo,Lee Jeong Eun,Choi Eun Young,Park Ju Young,Kim Tae-Hoon,Park Nayun,Jin Xiong,Jung Ji-Eun,Shin Daye,Hong Jun Hee,Kim Hyunggee,Yoo Heon,Lee Seung-Hoon,Kim Youn-Jae,Park Jong Bae,Kim Jong Heon
Brain : a journal of neurology
Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR-21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion in vitro and in vivo, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma.
10.1093/brain/awv167
Rapid Intraoperative Molecular Characterization of Glioma.
Shankar Ganesh M,Francis Joshua M,Rinne Mikael L,Ramkissoon Shakti H,Huang Franklin W,Venteicher Andrew S,Akama-Garren Elliot H,Kang Yun Jee,Lelic Nina,Kim James C,Brown Loreal E,Charbonneau Sarah K,Golby Alexandra J,Sekhar Pedamallu Chandra,Hoang Mai P,Sullivan Ryan J,Cherniack Andrew D,Garraway Levi A,Stemmer-Rachamimov Anat,Reardon David A,Wen Patrick Y,Brastianos Priscilla K,Curry William T,Barker Fred G,Hahn William C,Nahed Brian V,Ligon Keith L,Louis David N,Cahill Daniel P,Meyerson Matthew
JAMA oncology
IMPORTANCE:Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS:This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%-99%) and 100% specificity (95% CI, 95%-100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE:The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations.
10.1001/jamaoncol.2015.0917
Bringing IDH into the Fold.
Zadeh Gelareh,Aldape Kenneth
Cancer cell
Glioma-associated mutations in IDH1 or IDH2 lead to aberrant DNA methylation. A recent paper shows that loss of methylation-sensitive CTCF binding in IDH mutant cells leads to disruption of enhancer boundary function, which results in aberrant activation of PDGFRA expression via an enhancer associated with an adjacent gene.
10.1016/j.ccell.2016.01.010
-Mutant Tumors Vulnerable to PARP Inhibition.
Cancer discovery
Several cancers, including glioma and acute myeloid leukemia, carry mutations in or Researchers have found that these mutations impair homologous recombination, making the tumors sensitive to PARP inhibition. They showed that one such inhibitor, olaparib, killed -mutant cancer cells in culture and slowed tumor growth in mice.
10.1158/2159-8290.CD-NB2017-026
Insights From Molecular Profiling of Adult Glioma.
Diamandis Phedias,Aldape Kenneth D
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
The comprehensive molecular profiling of cancer has resulted in new insights into the biology and classification of numerous tumor types. In the case of primary brain tumors that commonly affect adults, an emerging set of disease-defining biomarker sets is reshaping existing diagnostic entities that had previously been defined on the basis of their microscopic appearance. Substantial progress has been made in this regard for common primary brain tumors in adults, especially diffuse gliomas, where large-scale profiling efforts have led to the incorporation of highly prevalent molecular alterations that promote a biologically based classification as an adjunct to the traditional histopathologic approach. The growing awareness that histologically indistinguishable tumors can be divided into more precise and biologically relevant subgroups has demanded a more global routine approach to biomarker assessment. These considerations have begun to intersect with the decreasing costs and availability of genome-wide analysis tools and, thus, incorporation into routine practice. We review how molecular profiling already has led to an evolution in the classification of brain tumors. In addition, we discuss the likely trajectory of incorporation of global molecular profiling platforms into the routine clinical classification of adult brain tumors.
10.1200/JCO.2017.73.9516
Thymosin β 4 gene silencing decreases stemness and invasiveness in glioblastoma.
Wirsching Hans-Georg,Krishnan Shanmugarajan,Florea Ana-Maria,Frei Karl,Krayenbühl Niklaus,Hasenbach Kathy,Reifenberger Guido,Weller Michael,Tabatabai Ghazaleh
Brain : a journal of neurology
Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. Thymosin beta 4 gene silencing promotes differentiation of neural stem cells whereas thymosin beta 4 overexpression initiates cortical folding of developing brain hemispheres. A role of thymosin beta 4 in malignant gliomas has not yet been investigated. We analysed thymosin beta 4 staining on tissue microarrays and performed interrogations of the REMBRANDT and the Cancer Genome Atlas databases. We investigated thymosin beta 4 expression in seven established glioma cell lines and seven glioma-initiating cell lines and induced or silenced thymosin beta 4 expression by lentiviral transduction in LNT-229, U87MG and GS-2 cells to study the effects of altered thymosin beta 4 expression on gene expression, growth, clonogenicity, migration, invasion, self-renewal and differentiation capacity in vitro, and tumorigenicity in vivo. Thymosin beta 4 expression increased with grade of malignancy in gliomas. Thymosin beta 4 gene silencing in LNT-229 and U87MG glioma cells inhibited migration and invasion, promoted starvation-induced cell death in vitro and enhanced survival of glioma-bearing mice. Thymosin beta 4 gene silencing in GS-2 cells inhibited self-renewal and promoted differentiation in vitro and decreased tumorigenicity in vivo. Gene expression analysis suggested a thymosin beta 4-dependent regulation of mesenchymal signature genes and modulation of TGFβ and p53 signalling networks. We conclude that thymosin beta 4 should be explored as a novel molecular target for anti-glioma therapy.
10.1093/brain/awt333
Tails of a Super Histone.
Sin-Chan Patrick,Mumal Iqra,Huang Annie
Cancer cell
Diffuse intrinsic brain stem gliomas (DIPGs) with characteristic K27M mutation of H3.3 are lethal and poorly understood childhood cancers. In this issue of Cancer Cell, Larson et al. exploit a unique murine DIPG model with inducible, endogenous K27M expression to reveal insights into mechanisms of K27M-mediated transformation in DIPG.
10.1016/j.ccell.2018.12.005
Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling.
Wu Yingwei,Fan Qi,Zeng Feng,Zhu Jinyu,Chen Jian,Fan Dandan,Li Xinwei,Duan Wenjia,Guo Qinghua,Cao Zhonglian,Briley-Saebo Karen,Li Cong,Tao Xiaofeng
Nano letters
Malignant gliomas are the most common primary brain tumors and are associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in approximately 30% of glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the binding affinity of the free peptide ( K = 3.96 × 10 M), the binding affinity of the nanoinhibitor to MET increased 3 orders of magnitude to 1.32 × 10 M. This nanoinhibitor efficiently reduced the proliferation and invasion of human glioblastoma U87MG cells in vitro by blocking MET signaling with remarkably attenuated levels of phosphorylated MET ( pMET) and its downstream signaling proteins, such as pAKT and pERK1/2. Although no obvious therapeutic effect was observed after treatment with free cBMP peptide, in vivo T2-weighted magnetic resonance imaging (MRI) showed a significant delay in tumor growth after intravenous injection of the nanoinhibitor. The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials. Immunoblotting studies of tumor homogenate verified that the nanoinhibitor restrained glioma growth by blocking MET downstream signaling. pMET and its downstream proteins pAKT and pERK1/2, which are involved in the survival and invasion of cancer cells, decreased in the nanoinhibitor-treated group by 44.2%, 62.2%, and 32.3%, respectively, compared with those in the control group. In summary, we developed a peptide-functionalized MET nanoinhibitor that showed extremely high binding affinity to MET and effectively inhibited glioma growth by blocking MET downstream signaling. To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling with a novel nanoinhibitor. Compared to antibodies and chemical inhibitors in clinical trials, the nanoinhibitor blocks MET signaling and provides a new approach for the treatment of glioma with the advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance.
10.1021/acs.nanolett.8b01879
Mutant IDH1 and thrombosis in gliomas.
Acta neuropathologica
Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.
10.1007/s00401-016-1620-7
Acyl-CoA-Binding Protein Fuels Gliomagenesis.
Bi Junfeng,Mischel Paul S
Cell metabolism
Altered lipid metabolism is common in glioblastoma, but its role in tumorigenesis is not well understood. In this issue of Cell Metabolism, Duman et al. (2019) provide new insight into this process, demonstrating that acyl-CoA-binding protein (ACBP) drives glioblastoma growth by promoting mitochondrial long fatty acyl-CoA accumulation and β-oxidation.
10.1016/j.cmet.2019.07.007
Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment.
Park Jin-Sung,Kim Il-Kug,Han Sangyeul,Park Intae,Kim Chan,Bae Jeomil,Oh Seung Ja,Lee Seungjoo,Kim Jeong Hoon,Woo Dong-Cheol,He Yulong,Augustin Hellmut G,Kim Injune,Lee Doheon,Koh Gou Young
Cancer cell
A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.
10.1016/j.ccell.2016.10.018
Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop.
Nature neuroscience
Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133Notch1, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.
10.1038/s41593-018-0285-z
The Power of Human Cancer Genetics as Revealed by Low-Grade Gliomas.
Annual review of genetics
The human brain contains a vast number of cells and shows extraordinary cellular diversity to facilitate the many cognitive and automatic commands governing our bodily functions. This complexity arises partly from large-scale structural variations in the genome, evolutionary processes to increase brain size, function, and cognition. Not surprisingly given recent technical advances, low-grade gliomas (LGGs), which arise from the glia (the most abundant cell type in the brain), have undergone a recent revolution in their classification and therapy, especially in the pediatric setting. Next-generation sequencing has uncovered previously unappreciated diverse LGG entities, unraveling genetic subgroups and multiple molecular alterations and altered pathways, including many amenable to therapeutic targeting. In this article we review these novel entities, in which oncogenic processes show striking age-related neuroanatomical specificity (highlighting their close interplay with development); the opportunities they provide for targeted therapies, some of which are already practiced at the bedside; and the challenges of implementing molecular pathology in the clinic.
10.1146/annurev-genet-120417-031642
Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis.
Poon Candice C,Sarkar Susobhan,Yong V Wee,Kelly John J P
Brain : a journal of neurology
Glioblastoma is the most common and most malignant primary adult human brain tumour. Diagnosis of glioblastoma carries a dismal prognosis. Treatment resistance and tumour recurrence are the result of both cancer cell proliferation and their interaction with the tumour microenvironment. A large proportion of the tumour microenvironment consists of an inflammatory infiltrate predominated by microglia and macrophages, which are thought to be subverted by glioblastoma cells for tumour growth. Thus, glioblastoma-associated microglia and macrophages are logical therapeutic targets. Their emerging roles in glioblastoma progression are reflected in the burgeoning research into therapeutics directed at their modification or elimination. Here, we review the biology of glioblastoma-associated microglia and macrophages, and model systems used to study these cells in vitro and in vivo. We discuss translation of results using these model systems and review recent advances in immunotherapies targeting microglia and macrophages in glioblastoma. Significant challenges remain but medications that affect glioblastoma-associated microglia and macrophages hold considerable promise to improve the prognosis for patients with this disease.
10.1093/brain/aww355
A neurocentric perspective on glioma invasion.
Nature reviews. Neuroscience
Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood-brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease.
10.1038/nrn3765
Metabolic Reprogramming in Brain Tumors.
Venneti Sriram,Thompson Craig B
Annual review of pathology
Next-generation sequencing has substantially enhanced our understanding of the genetics of primary brain tumors by uncovering several novel driver genetic alterations. How many of these genetic modifications contribute to the pathogenesis of brain tumors is not well understood. An exciting paradigm emerging in cancer biology is that oncogenes actively reprogram cellular metabolism to enable tumors to survive and proliferate. We discuss how some of these genetic alterations in brain tumors rewire metabolism. Furthermore, metabolic alterations directly impact epigenetics well beyond classical mechanisms of tumor pathogenesis. Metabolic reprogramming in brain tumors is also influenced by the tumor microenvironment contributing to drug resistance and tumor recurrence. Altered cancer metabolism can be leveraged to noninvasively image brain tumors, which facilitates improved diagnosis and the evaluation of treatment effectiveness. Many of these aspects of altered metabolism provide novel therapeutic opportunities to effectively treat primary brain tumors.
10.1146/annurev-pathol-012615-044329
Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis.
Glasgow Stacey M,Carlson Jeffrey C,Zhu Wenyi,Chaboub Lesley S,Kang Peng,Lee Hyun Kyoung,Clovis Yoanne M,Lozzi Brittney E,McEvilly Robert J,Rosenfeld Michael G,Creighton Chad J,Lee Soo-Kyung,Mohila Carrie A,Deneen Benjamin
Nature neuroscience
Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long-range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo. Complementary genetic studies found that Sox9-Brn2 and Isl1-Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS.
10.1038/nn.4638
Spatial heterogeneity in medulloblastoma.
Morrissy A Sorana,Cavalli Florence M G,Remke Marc,Ramaswamy Vijay,Shih David J H,Holgado Borja L,Farooq Hamza,Donovan Laura K,Garzia Livia,Agnihotri Sameer,Kiehna Erin N,Mercier Eloi,Mayoh Chelsea,Papillon-Cavanagh Simon,Nikbakht Hamid,Gayden Tenzin,Torchia Jonathon,Picard Daniel,Merino Diana M,Vladoiu Maria,Luu Betty,Wu Xiaochong,Daniels Craig,Horswell Stuart,Thompson Yuan Yao,Hovestadt Volker,Northcott Paul A,Jones David T W,Peacock John,Wang Xin,Mack Stephen C,Reimand Jüri,Albrecht Steffen,Fontebasso Adam M,Thiessen Nina,Li Yisu,Schein Jacqueline E,Lee Darlene,Carlsen Rebecca,Mayo Michael,Tse Kane,Tam Angela,Dhalla Noreen,Ally Adrian,Chuah Eric,Cheng Young,Plettner Patrick,Li Haiyan I,Corbett Richard D,Wong Tina,Long William,Loukides James,Buczkowicz Pawel,Hawkins Cynthia E,Tabori Uri,Rood Brian R,Myseros John S,Packer Roger J,Korshunov Andrey,Lichter Peter,Kool Marcel,Pfister Stefan M,Schüller Ulrich,Dirks Peter,Huang Annie,Bouffet Eric,Rutka James T,Bader Gary D,Swanton Charles,Ma Yusanne,Moore Richard A,Mungall Andrew J,Majewski Jacek,Jones Steven J M,Das Sunit,Malkin David,Jabado Nada,Marra Marco A,Taylor Michael D
Nature genetics
Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
10.1038/ng.3838
The landscape of the mesenchymal signature in brain tumours.
Behnan Jinan,Finocchiaro Gaetano,Hanna Gabi
Brain : a journal of neurology
The complexity of glioblastoma multiforme, the most common and lethal variant of gliomas, is reflected by cellular and molecular heterogeneity at both the inter- and intra-tumoural levels. Molecular subtyping has arisen in the past two decades as a promising strategy to give better predictions of glioblastoma multiforme evolution, common disease pathways, and rational treatment options. The Cancer Genome Atlas network initially identified four molecular subtypes of glioblastoma multiforme: proneural, neural, mesenchymal and classical. However, further studies, also investigated glioma stem cells, have only identified two to three subtypes: proneural, mesenchymal and classical. The proneural-mesenchymal transition upon tumour recurrence has been suggested as a mechanism of tumour resistance to radiation and chemotherapy treatment. Glioblastoma multiforme patients with the mesenchymal subtype tend to survive shorter than other subtypes when analysis is restricted to samples with low transcriptional heterogeneity. Although the mesenchymal signature in malignant glioma may seem at odds with the common idea of the ectodermal origin of neural-glial lineages, the presence of the mesenchymal signature in glioma is supported by several studies suggesting that it can result from: (i) intrinsic expression of tumour cells affected with accumulated genetic mutations and cell of origin; (ii) tumour micro-environments with recruited macrophages or microglia, mesenchymal stem cells or pericytes, and other progenitors; (iii) resistance to tumour treatment, including radiotherapy, antiangiogenic therapy and possibly chemotherapy. Genetic abnormalities, mainly NF1 mutations, together with NF-κB transcriptional programs, are the main driver of acquiring mesenchymal-signature. This signature is far from being simply tissue artefacts, as it has been identified in single cell glioma, circulating tumour cells, and glioma stem cells that are released from the tumour micro-environment. All these together suggest that the mesenchymal signature in glioblastoma multiforme is induced and sustained via cell intrinsic mechanisms and tumour micro-environment factors. Although patients with the mesenchymal subtype tend to have poorer prognosis, they may have favourable response to immunotherapy and intensive radio- and chemotherapy.
10.1093/brain/awz044
Mutations in chromatin machinery and pediatric high-grade glioma.
Lulla Rishi R,Saratsis Amanda Muhs,Hashizume Rintaro
Science advances
Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors.
10.1126/sciadv.1501354
Medulloblastoma: From Molecular Subgroups to Molecular Targeted Therapies.
Wang Jun,Garancher Alexandra,Ramaswamy Vijay,Wechsler-Reya Robert J
Annual review of neuroscience
Brain tumors are the leading cause of cancer-related death in children, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Advances in surgery, radiation, and chemotherapy have improved the survival of MB patients. But despite these advances, 25-30% of patients still die from the disease, and survivors suffer severe long-term side effects from the aggressive therapies they receive. Although MB is often considered a single disease, molecular profiling has revealed a significant degree of heterogeneity, and there is a growing consensus that MB consists of multiple subgroups with distinct driver mutations, cells of origin, and prognosis. Here, we review recent progress in MB research, with a focus on the genes and pathways that drive tumorigenesis, the animal models that have been developed to study tumor biology, and the advances in conventional and targeted therapy.
10.1146/annurev-neuro-070815-013838
SnapShot: Medulloblastoma.
Rusert Jessica M,Wu Xiaochong,Eberhart Charles G,Taylor Michael D,Wechsler-Reya Robert J
Cancer cell
Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the classification of MB subgroups, historically by histopathology and currently based on genomic information. Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy.
10.1016/j.ccell.2014.11.015
GPD1 Specifically Marks Dormant Glioma Stem Cells with a Distinct Metabolic Profile.
Rusu Patricia,Shao Chunxuan,Neuerburg Anna,Acikgöz Azer Aylin,Wu Yonghe,Zou Peng,Phapale Prasad,Shankar Tchirupura S,Döring Kristina,Dettling Steffen,Körkel-Qu Huiqin,Bekki Gözde,Costa Barbara,Guo Te,Friesen Olga,Schlotter Magdalena,Heikenwalder Mathias,Tschaharganeh Darjus F,Bukau Bernd,Kramer Günter,Angel Peter,Herold-Mende Christel,Radlwimmer Bernhard,Liu Hai-Kun
Cell stem cell
Brain tumor stem cells (BTSCs) are a chemoresistant population that can drive tumor growth and relapse, but the lack of BTSC-specific markers prevents selective targeting that spares resident stem cells. Through a ribosome-profiling analysis of mouse neural stem cells (NSCs) and BTSCs, we find glycerol-3-phosphate dehydrogenase 1 (GPD1) expression specifically in BTSCs and not in NSCs. GPD1 expression is present in the dormant BTSC population, which is enriched at tumor borders and drives tumor relapse after chemotherapy. GPD1 inhibition prolongs survival in mouse models of glioblastoma in part through altering cellular metabolism and protein translation, compromising BTSC maintenance. Metabolomic and lipidomic analyses confirm that GPD1 BTSCs have a profile distinct from that of NSCs, which is dependent on GPD1 expression. Similar GPD1 expression patterns and prognostic associations are observed in human gliomas. This study provides an attractive therapeutic target for treating brain tumors and new insights into mechanisms regulating BTSC dormancy.
10.1016/j.stem.2019.06.004
Acyl-CoA-Binding Protein Drives Glioblastoma Tumorigenesis by Sustaining Fatty Acid Oxidation.
Duman Ceren,Yaqubi Kaneschka,Hoffmann Angelika,Acikgöz Azer Aylin,Korshunov Andrey,Bendszus Martin,Herold-Mende Christel,Liu Hai-Kun,Alfonso Julieta
Cell metabolism
Glioblastoma multiforme (GBM) undergoes metabolic reprogramming to meet the high ATP and anabolic demands of the tumor cells. However, the role of fatty acid oxidation (FAO) and its regulators in the GBM context has been largely unknown. Here, we show that the neural stem cell pro-proliferative factor acyl-CoA-binding protein (ACBP, also known as DBI) is highly expressed in GBM, and by binding to acyl-CoAs, it cell-autonomously maintains high proliferation rates, promoting tumor growth and poor survival in several preclinical models. Mechanistic experiments using ACBP-acyl-CoA binding affinity variants and pharmacological FAO modulators suggest that ACBP supports tumor growth by controlling the availability of long-chain fatty acyl-CoAs to mitochondria, promoting FAO in GBM. Thus, our findings uncover a critical link between lipid metabolism and GBM progression established by ACBP and offer a potential therapeutic strategy for an effective anti-proliferative metabolic management of GBM.
10.1016/j.cmet.2019.04.004
Surgical oncology for gliomas: the state of the art.
Sanai Nader,Berger Mitchel S
Nature reviews. Clinical oncology
Surgical resection remains the mainstay of treatment for patients with glioma of any grade. Maximal resection of the tumour is central to achieving long-term disease control; however, the relationship between the extent of glioma resection and actual clinical benefit for the patient is predicated on the balance between cytoreduction and neurological morbidity. For the neurosurgical oncologist, the clinical rationale for undertaking increasingly extensive resections has gained traction. In parallel, novel surgical techniques and technologies have been developed that help improve patient outcomes. During the past decade, neurosurgeons have leveraged advanced intraoperative imaging methods, fluorescence-based tumour biomarkers, and real-time mutational analyses to maximize the extent of tumour resection. In addition, approaches to minimizing the risk of perioperative morbidity continue to be improved through the combined use of stimulation-mapping techniques, corticospinal tract imaging, and stereotactic thermal ablation. Taken together, these modern principles of neurosurgical oncology bear little resemblance to historical therapeutic strategies for patients with glioma and have dramatically altered the approach to the treatment of patients with these brain tumours. Herein, we outline the state of the art in surgical oncology for gliomas.
10.1038/nrclinonc.2017.171
Multiomic Medulloblastomas.
Cancer cell
Epigenomics and transcriptomics of medulloblastoma-an important childhood brain tumor-segregate the disease into four clinically relevant subtypes. In this issue of Cancer Cell, Archer et al. and Forget et al. add the proteome to our multiomic map of this disease, revealing posttranscriptional and posttranslational variations with potential therapeutic implications.
10.1016/j.ccell.2018.08.010
Emerging intersections between neuroscience and glioma biology.
Nature neuroscience
The establishment of neuronal and glial networks in the brain depends on the activities of neural progenitors, which are influenced by cell-intrinsic mechanisms, interactions with the local microenvironment and long-range signaling. Progress in neuroscience has helped identify key factors in CNS development. In parallel, studies in recent years have increased our understanding of molecular and cellular factors in the development and growth of primary brain tumors. To thrive, glioma cells exploit pathways that are active in normal CNS progenitor cells, as well as in normal neurotransmitter signaling. Furthermore, tumor cells of incurable gliomas integrate into communicating multicellular networks, where they are interconnected through neurite-like cellular protrusions. In this Review, we discuss evidence that CNS development, organization and function share a number of common features with glioma progression and malignancy. These include mechanisms used by cells to proliferate and migrate, interact with their microenvironment and integrate into multicellular networks. The emerging intersections between the fields of neuroscience and neuro-oncology considered in this review point to new research directions and novel therapeutic opportunities.
10.1038/s41593-019-0540-y
Identification of diverse astrocyte populations and their malignant analogs.
Nature neuroscience
Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting-based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to synaptogenesis and tumor pathophysiology, providing a blueprint for understanding diverse astrocyte contributions to neurological disease.
10.1038/nn.4493
2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.
Science translational medicine
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.
10.1126/scitranslmed.aal2463
Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.
Castel David,Philippe Cathy,Calmon Raphaël,Le Dret Ludivine,Truffaux Nathalène,Boddaert Nathalie,Pagès Mélanie,Taylor Kathryn R,Saulnier Patrick,Lacroix Ludovic,Mackay Alan,Jones Chris,Sainte-Rose Christian,Blauwblomme Thomas,Andreiuolo Felipe,Puget Stephanie,Grill Jacques,Varlet Pascale,Debily Marie-Anne
Acta neuropathologica
Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.
10.1007/s00401-015-1478-0
Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers.
Korshunov Andrey,Ryzhova Marina,Hovestadt Volker,Bender Sebastian,Sturm Dominik,Capper David,Meyer Jochen,Schrimpf Daniel,Kool Marcel,Northcott Paul A,Zheludkova Olga,Milde Till,Witt Olaf,Kulozik Andreas E,Reifenberger Guido,Jabado Nada,Perry Arie,Lichter Peter,von Deimling Andreas,Pfister Stefan M,Jones David T W
Acta neuropathologica
Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease.
10.1007/s00401-015-1405-4
cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant.
Louis David N,Giannini Caterina,Capper David,Paulus Werner,Figarella-Branger Dominique,Lopes M Beatriz,Batchelor Tracy T,Cairncross J Gregory,van den Bent Martin,Wick Wolfgang,Wesseling Pieter
Acta neuropathologica
10.1007/s00401-018-1826-y
A glial blueprint for gliomagenesis.
Laug Dylan,Glasgow Stacey M,Deneen Benjamin
Nature reviews. Neuroscience
Gliomas are heterogeneous tumours derived from glial cells and remain the deadliest form of brain cancer. Although the glioma stem cell sits at the apex of the cellular hierarchy, how it produces the vast cellular constituency associated with frank glioma remains poorly defined. We explore glioma tumorigenesis through the lens of glial development, starting with the neurogenic-gliogenic switch and progressing through oligodendrocyte and astrocyte differentiation. Beginning with the factors that influence normal glial linage progression and diversity, a pattern emerges that has useful parallels in the development of glioma and may ultimately provide targetable pathways for much-needed new therapeutics.
10.1038/s41583-018-0014-3
Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy.
Zhou Wenchao,Chen Cong,Shi Yu,Wu Qiulian,Gimple Ryan C,Fang Xiaoguang,Huang Zhi,Zhai Kui,Ke Susan Q,Ping Yi-Fang,Feng Hua,Rich Jeremy N,Yu Jennifer S,Bao Shideng,Bian Xiu-Wu
Cell stem cell
The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.
10.1016/j.stem.2017.10.002
Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence.
Xue Jingwei,Zhao Zekai,Zhang Lei,Xue Lingjing,Shen Shiyang,Wen Yajing,Wei Zhuoyuan,Wang Lu,Kong Lingyi,Sun Hongbin,Ping Qineng,Mo Ran,Zhang Can
Nature nanotechnology
Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.
10.1038/nnano.2017.54
Oligodendroglioma: pathology, molecular mechanisms and markers.
Wesseling Pieter,van den Bent Martin,Perry Arie
Acta neuropathologica
For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for the diagnosis of 'canonical oligodendroglioma'. This transition to an integrated morphological and molecular diagnosis may result in the disappearance of oligoastrocytoma as an entity, but brings new challenges as well. For instance it needs to be sorted out how (histopathological) criteria for grading of 'canonical oligodendrogliomas' should be adapted, how pediatric oligodendrogliomas (known to lack codeletions) should be defined, which platforms and cut-off levels should ideally be used for demonstration of particular molecular aberrations, and how the diagnosis of oligodendroglioma should be made in centers/countries where molecular diagnostics is not available. Meanwhile, smart integration of morphological and molecular information will lead to recognition of biologically much more uniform groups within the spectrum of diffuse gliomas and thereby facilitate tailored treatments for individual patients.
10.1007/s00401-015-1424-1
Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma.
Nature cell biology
L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes.
10.1038/ncb3272
Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression.
Wang Xiuxing,Prager Briana C,Wu Qiulian,Kim Leo J Y,Gimple Ryan C,Shi Yu,Yang Kailin,Morton Andrew R,Zhou Wenchao,Zhu Zhe,Obara Elisabeth Anne Adanma,Miller Tyler E,Song Anne,Lai Sisi,Hubert Christopher G,Jin Xun,Huang Zhi,Fang Xiaoguang,Dixit Deobrat,Tao Weiwei,Zhai Kui,Chen Cong,Dong Zhen,Zhang Guoxin,Dombrowski Stephen M,Hamerlik Petra,Mack Stephen C,Bao Shideng,Rich Jeremy N
Cell stem cell
Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.
10.1016/j.stem.2018.03.011
Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment.
Müller Sören,Kohanbash Gary,Liu S John,Alvarado Beatriz,Carrera Diego,Bhaduri Aparna,Watchmaker Payal B,Yagnik Garima,Di Lullo Elizabeth,Malatesta Martina,Amankulor Nduka M,Kriegstein Arnold R,Lim Daniel A,Aghi Manish,Okada Hideho,Diaz Aaron
Genome biology
BACKGROUND:Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. RESULTS:We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells. CONCLUSIONS:We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.
10.1186/s13059-017-1362-4
Origin of the U87MG glioma cell line: Good news and bad news.
Allen Marie,Bjerke Mia,Edlund Hanna,Nelander Sven,Westermark Bengt
Science translational medicine
Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.
10.1126/scitranslmed.aaf6853
Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis.
Cell stem cell
The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.
10.1016/j.stem.2019.03.006
Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors.
Cancer cell
Aggressive cancers such as glioblastoma (GBM) contain intermingled apoptotic cells adjacent to proliferating tumor cells. Nonetheless, intercellular signaling between apoptotic and surviving cancer cells remain elusive. In this study, we demonstrate that apoptotic GBM cells paradoxically promote proliferation and therapy resistance of surviving tumor cells by secreting apoptotic extracellular vesicles (apoEVs) enriched with various components of spliceosomes. apoEVs alter RNA splicing in recipient cells, thereby promoting their therapy resistance and aggressive migratory phenotype. Mechanistically, we identified RBM11 as a representative splicing factor that is upregulated in tumors after therapy and shed in extracellular vesicles upon induction of apoptosis. Once internalized in recipient cells, exogenous RBM11 switches splicing of MDM4 and Cyclin D1 toward the expression of more oncogenic isoforms.
10.1016/j.ccell.2018.05.012
Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair.
Ma Jianhui,Benitez Jorge A,Li Jie,Miki Shunichiro,Ponte de Albuquerque Claudio,Galatro Thais,Orellana Laura,Zanca Ciro,Reed Rachel,Boyer Antonia,Koga Tomoyuki,Varki Nissi M,Fenton Tim R,Nagahashi Marie Suely Kazue,Lindahl Erik,Gahman Timothy C,Shiau Andrew K,Zhou Huilin,DeGroot John,Sulman Erik P,Cavenee Webster K,Kolodner Richard D,Chen Clark C,Furnari Frank B
Cancer cell
Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.
10.1016/j.ccell.2019.01.020
Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.
Cancer cell
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
10.1016/j.ccell.2019.04.004
IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response.
Núñez Felipe J,Mendez Flor M,Kadiyala Padma,Alghamri Mahmoud S,Savelieff Masha G,Garcia-Fabiani Maria B,Haase Santiago,Koschmann Carl,Calinescu Anda-Alexandra,Kamran Neha,Saxena Meghna,Patel Rohin,Carney Stephen,Guo Marissa Z,Edwards Marta,Ljungman Mats,Qin Tingting,Sartor Maureen A,Tagett Rebecca,Venneti Sriram,Brosnan-Cashman Jacqueline,Meeker Alan,Gorbunova Vera,Zhao Lili,Kremer Daniel M,Zhang Li,Lyssiotis Costas A,Jones Lindsey,Herting Cameron J,Ross James L,Hambardzumyan Dolores,Hervey-Jumper Shawn,Figueroa Maria E,Lowenstein Pedro R,Castro Maria G
Science translational medicine
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1) are younger at diagnosis and live longer. mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 ) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1 mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1, and inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1 in the context of TP53 and ATRX loss. We discovered that IDH1 expression in the genetic context of and gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1 glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.
10.1126/scitranslmed.aaq1427
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate.
Nature medicine
The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.
10.1038/s41591-018-0095-6
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.
Grasso Catherine S,Tang Yujie,Truffaux Nathalene,Berlow Noah E,Liu Lining,Debily Marie-Anne,Quist Michael J,Davis Lara E,Huang Elaine C,Woo Pamelyn J,Ponnuswami Anitha,Chen Spenser,Johung Tessa B,Sun Wenchao,Kogiso Mari,Du Yuchen,Qi Lin,Huang Yulun,Hütt-Cabezas Marianne,Warren Katherine E,Le Dret Ludivine,Meltzer Paul S,Mao Hua,Quezado Martha,van Vuurden Dannis G,Abraham Jinu,Fouladi Maryam,Svalina Matthew N,Wang Nicholas,Hawkins Cynthia,Nazarian Javad,Alonso Marta M,Raabe Eric H,Hulleman Esther,Spellman Paul T,Li Xiao-Nan,Keller Charles,Pal Ranadip,Grill Jacques,Monje Michelle
Nature medicine
Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.
10.1038/nm.3855
MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma.
Huang Tianzhi,Kim Chung Kwon,Alvarez Angel A,Pangeni Rajendra P,Wan Xuechao,Song Xiao,Shi Taiping,Yang Yongyong,Sastry Namratha,Horbinski Craig M,Lu Songjian,Stupp Roger,Kessler John A,Nishikawa Ryo,Nakano Ichiro,Sulman Erik P,Lu Xinghua,James Charles David,Yin Xiao-Ming,Hu Bo,Cheng Shi-Yuan
Cancer cell
ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.
10.1016/j.ccell.2017.11.005
Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression.
Larson Jon D,Kasper Lawryn H,Paugh Barbara S,Jin Hongjian,Wu Gang,Kwon Chang-Hyuk,Fan Yiping,Shaw Timothy I,Silveira André B,Qu Chunxu,Xu Raymond,Zhu Xiaoyan,Zhang Junyuan,Russell Helen R,Peters Jennifer L,Finkelstein David,Xu Beisi,Lin Tong,Tinkle Christopher L,Patay Zoltan,Onar-Thomas Arzu,Pounds Stanley B,McKinnon Peter J,Ellison David W,Zhang Jinghui,Baker Suzanne J
Cancer cell
Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Neonatal induction of H3.3 K27M cooperated with activating platelet-derived growth factor receptor α (PDGFRα) mutant and Trp53 loss to accelerate development of diffuse brainstem gliomas that recapitulated human DIPG gene expression signatures and showed global changes in H3K27 posttranslational modifications, but relatively restricted gene expression changes. Genes upregulated in H3.3 K27M tumors were enriched for those associated with neural development where H3K27me3 loss released the poised state of apparently bivalent promoters, whereas downregulated genes were enriched for those encoding homeodomain transcription factors.
10.1016/j.ccell.2018.11.015
Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling.
Gimple Ryan C,Kidwell Reilly L,Kim Leo J Y,Sun Tengqian,Gromovsky Anthony D,Wu Qiulian,Wolf Megan,Lv Deguan,Bhargava Shruti,Jiang Li,Prager Briana C,Wang Xiuxing,Ye Qing,Zhu Zhe,Zhang Guoxin,Dong Zhen,Zhao Linjie,Lee Derrick,Bi Junfeng,Sloan Andrew E,Mischel Paul S,Brown J Mark,Cang Hu,Huan Tao,Mack Stephen C,Xie Qi,Rich Jeremy N
Cancer discovery
Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs. SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy...
10.1158/2159-8290.CD-19-0061
Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma.
McBrayer Samuel K,Mayers Jared R,DiNatale Gabriel J,Shi Diana D,Khanal Januka,Chakraborty Abhishek A,Sarosiek Kristopher A,Briggs Kimberly J,Robbins Alissa K,Sewastianik Tomasz,Shareef Sarah J,Olenchock Benjamin A,Parker Seth J,Tateishi Kensuke,Spinelli Jessica B,Islam Mirazul,Haigis Marcia C,Looper Ryan E,Ligon Keith L,Bernstein Bradley E,Carrasco Ruben D,Cahill Daniel P,Asara John M,Metallo Christian M,Yennawar Neela H,Vander Heiden Matthew G,Kaelin William G
Cell
IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.
10.1016/j.cell.2018.08.038
Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.
Gholamin Sharareh,Mitra Siddhartha S,Feroze Abdullah H,Liu Jie,Kahn Suzana A,Zhang Michael,Esparza Rogelio,Richard Chase,Ramaswamy Vijay,Remke Marc,Volkmer Anne K,Willingham Stephen,Ponnuswami Anitha,McCarty Aaron,Lovelace Patricia,Storm Theresa A,Schubert Simone,Hutter Gregor,Narayanan Cyndhavi,Chu Pauline,Raabe Eric H,Harsh Griffith,Taylor Michael D,Monje Michelle,Cho Yoon-Jae,Majeti Ravi,Volkmer Jens P,Fisher Paul G,Grant Gerald,Steinberg Gary K,Vogel Hannes,Edwards Michael,Weissman Irving L,Cheshier Samuel H
Science translational medicine
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.
10.1126/scitranslmed.aaf2968
Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance.
Shi Yu,Guryanova Olga A,Zhou Wenchao,Liu Chong,Huang Zhi,Fang Xiaoguang,Wang Xiuxing,Chen Cong,Wu Qiulian,He Zhicheng,Wang Wei,Zhang Wei,Jiang Tao,Liu Qing,Chen Yaping,Wang Wenying,Wu Jingjing,Kim Leo,Gimple Ryan C,Feng Hua,Kung Hsiang-Fu,Yu Jennifer S,Rich Jeremy N,Ping Yi-Fang,Bian Xiu-Wu,Bao Shideng
Science translational medicine
Glioblastoma (GBM) is the most lethal primary brain tumor and is highly resistant to current treatments. GBM harbors glioma stem cells (GSCs) that not only initiate and maintain malignant growth but also promote therapeutic resistance including radioresistance. Thus, targeting GSCs is critical for overcoming the resistance to improve GBM treatment. Because the bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is preferentially up-regulated in GSCs relative to nonstem tumor cells and the BMX-mediated activation of the signal transducer and activator of transcription 3 (STAT3) is required for maintaining GSC self-renewal and tumorigenic potential, pharmacological inhibition of BMX may suppress GBM growth and reduce therapeutic resistance. We demonstrate that BMX inhibition by ibrutinib potently disrupts GSCs, suppresses GBM malignant growth, and effectively combines with radiotherapy. Ibrutinib markedly disrupts the BMX-mediated STAT3 activation in GSCs but shows minimal effect on neural progenitor cells (NPCs) lacking BMX expression. Mechanistically, BMX bypasses the suppressor of cytokine signaling 3 (SOCS3)-mediated inhibition of Janus kinase 2 (JAK2), whereas NPCs dampen the JAK2-mediated STAT3 activation via the negative regulation by SOCS3, providing a molecular basis for targeting BMX by ibrutinib to specifically eliminate GSCs while preserving NPCs. Our preclinical data suggest that repurposing ibrutinib for targeting GSCs could effectively control GBM tumor growth both as monotherapy and as adjuvant with conventional therapies.
10.1126/scitranslmed.aah6816
Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.
Nagaraja Surya,Vitanza Nicholas A,Woo Pamelyn J,Taylor Kathryn R,Liu Fang,Zhang Lei,Li Meng,Meng Wei,Ponnuswami Anitha,Sun Wenchao,Ma Jie,Hulleman Esther,Swigut Tomek,Wysocka Joanna,Tang Yujie,Monje Michelle
Cancer cell
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.
10.1016/j.ccell.2017.03.011
Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse.
Cancer cell
Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2 progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2 progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2 progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.
10.1016/j.ccell.2019.07.009
Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth.
Zhou Wenchao,Ke Susan Q,Huang Zhi,Flavahan William,Fang Xiaoguang,Paul Jeremy,Wu Ling,Sloan Andrew E,McLendon Roger E,Li Xiaoxia,Rich Jeremy N,Bao Shideng
Nature cell biology
Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ₃ as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.
10.1038/ncb3090
Molecular characterization of histopathological ependymoma variants.
Neumann Julia E,Spohn Michael,Obrecht Denise,Mynarek Martin,Thomas Christian,Hasselblatt Martin,Dorostkar Mario M,Wefers Annika K,Frank Stephan,Monoranu Camelia-Maria,Koch Arend,Witt Hendrik,Kool Marcel,Pajtler Kristian W,Rutkowski Stefan,Glatzel Markus,Schüller Ulrich
Acta neuropathologica
According to the WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas, and RELA-fusion-positive ependymomas (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e., the clear cell, papillary, and tanycytic ependymoma. In parallel, global DNA methylation patterns distinguish nine molecular groups, some of which tightly overlap with histopathological subgroups. However, the match of the aforementioned histological variants to DNA methylation classes remains unclear. We analyzed histomorphology, clinical parameters, and global DNA methylation of tumors with the initial histological diagnoses of tanycytic (n = 12), clear cell (n = 14), or papillary ependymoma (n = 19). Forty percent of these tumors did not match to the epigenetic profile of ependymomas, using a previously published DNA methylation-based classifier for brain tumors. Instead, they were classified as low-grade glioma (n = 3), plexus tumor (n = 2), CNS high-grade neuroepithelial tumor with MN1 alteration (n = 2), papillary tumor of the pineal region (n = 2), neurocytoma (n = 1), or did not match to any known brain tumor methylation class (n = 8). Overall, integrated diagnosis had to be changed in 35.6% of cases as compared to the initial diagnosis. Among the tumors molecularly classified as ependymoma (27/45 cases), tanycytic ependymomas were mostly located in the spine (5/7 cases) and matched to spinal or myxopapillary ependymoma. 6/8 clear cell ependymomas were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas with a positive ependymoma match (12/19 cases) showed either a "papillary" (n = 5), a "trabecular" (n = 1), or a "pseudo-papillary" (n = 6) growth pattern. The papillary growth pattern was strongly associated with the methylation class B of posterior fossa ependymoma (PFB, 5/5 cases) and tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Tumors with pseudo-papillary histology matched to the methylation class of myxopapillary ependymoma (4/6 cases), whereas the trabecular case was anatomically and molecularly a spinal ependymoma. Our results show that the diagnosis of histological ependymoma variants is challenging and epigenetic profiles may improve diagnostic accuracy of these cases. Whereas clear cell and papillary ependymomas display correlations between localization, histology, and methylation, tanycytic ependymoma does not represent a molecularly distinct subgroup.
10.1007/s00401-019-02090-0
Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology.
Gutmann David H,Kettenmann Helmut
Neuron
One of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the past decade, it is now appreciated that these tumors are composed of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these noncancerous cell types, monocytes (microglia and macrophages) predominate. In this Review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy.
10.1016/j.neuron.2019.08.028
Pilocytic astrocytoma: pathology, molecular mechanisms and markers.
Acta neuropathologica
Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90%. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed.
10.1007/s00401-015-1410-7
Current Challenges and Opportunities in Treating Glioblastoma.
Pharmacological reviews
Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and "druggable" targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, , , , , , , , , , , , , , , , , , , , and that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.
10.1124/pr.117.014944
Mechanisms of immunotherapy resistance: lessons from glioblastoma.
Nature immunology
Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.
10.1038/s41590-019-0433-y
Altered cellular metabolism in gliomas - an emerging landscape of actionable co-dependency targets.
Nature reviews. Cancer
Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.
10.1038/s41568-019-0226-5
A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.
Cancer cell
Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2 oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2 glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.
10.1016/j.ccell.2018.03.020
Biological Role and Therapeutic Potential of IDH Mutations in Cancer.
Cancer cell
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.
10.1016/j.ccell.2018.04.011
Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma.
Chen Peiwen,Zhao Di,Li Jun,Liang Xin,Li Jiexi,Chang Andrew,Henry Verlene K,Lan Zhengdao,Spring Denise J,Rao Ganesh,Wang Y Alan,DePinho Ronald A
Cancer cell
Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.
10.1016/j.ccell.2019.05.003
mA Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program.
Zhang Sicong,Zhao Boxuan Simen,Zhou Aidong,Lin Kangyu,Zheng Shaoping,Lu Zhike,Chen Yaohui,Sulman Erik P,Xie Keping,Bögler Oliver,Majumder Sadhan,He Chuan,Huang Suyun
Cancer cell
The dynamic and reversible N-methyladenosine (mA) RNA modification installed and erased by N-methyltransferases and demethylases regulates gene expression and cell fate. We show that the mA demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and mA-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Furthermore, a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of mA methylation in glioblastoma.
10.1016/j.ccell.2017.02.013
Advances in the molecular genetics of gliomas - implications for classification and therapy.
Reifenberger Guido,Wirsching Hans-Georg,Knobbe-Thomsen Christiane B,Weller Michael
Nature reviews. Clinical oncology
Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.
10.1038/nrclinonc.2016.204
Cancer stem cells in glioblastoma.
Lathia Justin D,Mack Stephen C,Mulkearns-Hubert Erin E,Valentim Claudia L L,Rich Jeremy N
Genes & development
Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.
10.1101/gad.261982.115
The role of microglia and macrophages in glioma maintenance and progression.
Hambardzumyan Dolores,Gutmann David H,Kettenmann Helmut
Nature neuroscience
There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.
10.1038/nn.4185
Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
Wang Qianghu,Hu Baoli,Hu Xin,Kim Hoon,Squatrito Massimo,Scarpace Lisa,deCarvalho Ana C,Lyu Sali,Li Pengping,Li Yan,Barthel Floris,Cho Hee Jin,Lin Yu-Hsi,Satani Nikunj,Martinez-Ledesma Emmanuel,Zheng Siyuan,Chang Edward,Sauvé Charles-Etienne Gabriel,Olar Adriana,Lan Zheng D,Finocchiaro Gaetano,Phillips Joanna J,Berger Mitchel S,Gabrusiewicz Konrad R,Wang Guocan,Eskilsson Eskil,Hu Jian,Mikkelsen Tom,DePinho Ronald A,Muller Florian,Heimberger Amy B,Sulman Erik P,Nam Do-Hyun,Verhaak Roel G W
Cancer cell
We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4 T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8 T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.
10.1016/j.ccell.2017.06.003
Glioma.
Weller Michael,Wick Wolfgang,Aldape Ken,Brada Michael,Berger Mitchell,Pfister Stefan M,Nishikawa Ryo,Rosenthal Mark,Wen Patrick Y,Stupp Roger,Reifenberger Guido
Nature reviews. Disease primers
Gliomas are primary brain tumours that are thought to derive from neuroglial stem or progenitor cells. On the basis of their histological appearance, they have been traditionally classified as astrocytic, oligodendroglial or ependymal tumours and assigned WHO grades I-IV, which indicate different degrees of malignancy. Tremendous progress in genomic, transcriptomic and epigenetic profiling has resulted in new concepts of classifying and treating gliomas. Diffusely infiltrating gliomas in adults are now separated into three overarching tumour groups with distinct natural histories, responses to treatment and outcomes: isocitrate dehydrogenase (IDH)-mutant, 1p/19q co-deleted tumours with mostly oligodendroglial morphology that are associated with the best prognosis; IDH-mutant, 1p/19q non-co-deleted tumours with mostly astrocytic histology that are associated with intermediate outcome; and IDH wild-type, mostly higher WHO grade (III or IV) tumours that are associated with poor prognosis. Gliomas in children are molecularly distinct from those in adults, the majority being WHO grade I pilocytic astrocytomas characterized by circumscribed growth, favourable prognosis and frequent BRAF gene fusions or mutations. Ependymal tumours can be molecularly subdivided into distinct epigenetic subgroups according to location and prognosis. Although surgery, radiotherapy and alkylating agent chemotherapy are still the mainstay of treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles may ultimately improve outcome. For an illustrated summary of this Primer, visit: http://go.nature.com/TXY7Ri.
10.1038/nrdp.2015.17
let-7 MicroRNAs Regulate Microglial Function and Suppress Glioma Growth through Toll-Like Receptor 7.
Buonfiglioli Alice,Efe Ibrahim E,Guneykaya Dilansu,Ivanov Andranik,Huang Yimin,Orlowski Elisabeth,Krüger Christina,Deisz Rudolf A,Markovic Darko,Flüh Charlotte,Newman Andrew G,Schneider Ulf C,Beule Dieter,Wolf Susanne A,Dzaye Omar,Gutmann David H,Semtner Marcus,Kettenmann Helmut,Lehnardt Seija
Cell reports
Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma.
10.1016/j.celrep.2019.11.029