Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy.
The Journal of clinical investigation
Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
10.1172/JCI134402
ARID1A gene mutation in ovarian and endometrial cancers (Review).
Takeda Takashi,Banno Kouji,Okawa Ryuichiro,Yanokura Megumi,Iijima Moito,Irie-Kunitomi Haruko,Nakamura Kanako,Iida Miho,Adachi Masataka,Umene Kiyoko,Nogami Yuya,Masuda Kenta,Kobayashi Yusuke,Tominaga Eiichiro,Aoki Daisuke
Oncology reports
The AT-rich interacting domain‑containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome‑wide analyses with next‑generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis‑associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis‑associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis‑associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular‑targeted drug can inhibit proliferation of ARID1A‑mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.
10.3892/or.2015.4421
ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade.
Shen Jianfeng,Ju Zhenlin,Zhao Wei,Wang Lulu,Peng Yang,Ge Zhongqi,Nagel Zachary D,Zou Jun,Wang Chen,Kapoor Prabodh,Ma Xiangyi,Ma Ding,Liang Jiyong,Song Shumei,Liu Jinsong,Samson Leona D,Ajani Jaffer A,Li Guo-Min,Liang Han,Shen Xuetong,Mills Gordon B,Peng Guang
Nature medicine
ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.
10.1038/s41591-018-0012-z
Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma.
Nature cancer
Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that mutation creates a dependence on glutamine metabolism. SWI/SNF represses () and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents an effective therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as mutations.
10.1038/s43018-020-00160-x
Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis.
Cancer cell
ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation and in a humanized immunocompetent ARID1A mutant patient-derived OCCC mouse model. Our data indicate that inhibition of the mevalonate pathway simultaneously suppresses tumor cell growth and boosts antitumor immunity by promoting pyroptosis, which synergizes with ICB in suppressing ARID1A-mutated cancers.
10.1016/j.ccell.2023.03.002
Single-cell transcriptomic analysis of endometriosis.
Nature genetics
Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.
10.1038/s41588-022-01254-1
Targeting ARID1A mutations in cancer.
Mullen Jaren,Kato Shumei,Sicklick Jason K,Kurzrock Razelle
Cancer treatment reviews
Genes encoding SWI/SNF chromatin remodeling complex subunits are collectively mutated in approximately 20% of human cancers. ARID1A is a SWI/SNF subunit gene whose protein product binds DNA. ARID1A gene alterations result in loss of function. It is the most commonly mutated member of the SWI/SNF complex, being aberrant in ∼6% of cancers overall, including ovarian clear cell cancers (∼45% of patients) and uterine endometrioid cancers (∼37%). ARID1A has a crucial role in regulating gene expression that drives oncogenesis or tumor suppression. In particular, ARID1A participates in control of the PI3K/AKT/mTOR pathway, immune responsiveness to cancer, EZH2 methyltransferase activity, steroid receptor modulation, DNA damage checkpoints, and regulation of p53 targets and KRAS signaling. A variety of compounds may be of benefit in ARID1A-altered cancers: immune checkpoint blockade, and inhibitors of mTOR, EZH2, histone deacetylases, ATR and/or PARP. ARID1A alterations may also mediate resistance to platinum chemotherapy and estrogen receptor degraders/modulators.
10.1016/j.ctrv.2021.102287