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Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nature reviews. Clinical oncology Advances in molecular biology, microfluidics and bioinformatics have empowered the study of thousands or even millions of individual cells from malignant tumours at the single-cell level of resolution. This high-dimensional, multi-faceted characterization of the genomic, transcriptomic, epigenomic and proteomic features of the tumour and/or the associated immune and stromal cells enables the dissection of tumour heterogeneity, the complex interactions between tumour cells and their microenvironment, and the details of the evolutionary trajectory of each tumour. Single-cell transcriptomics, the ability to track individual T cell clones through paired sequencing of the T cell receptor genes and high-dimensional single-cell spatial analysis are all areas of particular relevance to immuno-oncology. Multidimensional biomarker signatures will increasingly be crucial to guiding clinical decision-making in each patient with cancer. High-dimensional single-cell technologies are likely to provide the resolution and richness of data required to generate such clinically relevant signatures in immuno-oncology. In this Perspective, we describe advances made using transformative single-cell analysis technologies, especially in relation to clinical response and resistance to immunotherapy, and discuss the growing utility of single-cell approaches for answering important research questions. 10.1038/s41571-020-00449-x
Cancer-associated fibroblasts in gastrointestinal cancer. Kobayashi Hiroki,Enomoto Atsushi,Woods Susan L,Burt Alastair D,Takahashi Masahide,Worthley Daniel L Nature reviews. Gastroenterology & hepatology The tumour microenvironment, also termed the tumour stroma or tumour mesenchyme, includes fibroblasts, immune cells, blood vessels and the extracellular matrix and substantially influences the initiation, growth and dissemination of gastrointestinal cancer. Cancer-associated fibroblasts (CAFs) are one of the critical components of the tumour mesenchyme and not only provide physical support for epithelial cells but also are key functional regulators in cancer, promoting and retarding tumorigenesis in a context-dependent manner. In this Review, we outline the emerging understanding of gastrointestinal CAFs with a particular emphasis on their origin and heterogeneity, as well as their function in cancer cell proliferation, tumour immunity, angiogenesis, extracellular matrix remodelling and drug resistance. Moreover, we discuss the clinical implications of CAFs as biomarkers and potential targets for prevention and treatment of patients with gastrointestinal cancer. 10.1038/s41575-019-0115-0
Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. Zhang Zeda,Karthaus Wouter R,Lee Young Sun,Gao Vianne R,Wu Chao,Russo Joshua W,Liu Menghan,Mota Jose Mauricio,Abida Wassim,Linton Eliot,Lee Eugine,Barnes Spencer D,Chen Hsuan-An,Mao Ninghui,Wongvipat John,Choi Danielle,Chen Xiaoping,Zhao Huiyong,Manova-Todorova Katia,de Stanchina Elisa,Taplin Mary-Ellen,Balk Steven P,Rathkopf Dana E,Gopalan Anuradha,Carver Brett S,Mu Ping,Jiang Xuejun,Watson Philip A,Sawyers Charles L Cancer cell Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies. 10.1016/j.ccell.2020.06.005
Interferon-γ: teammate or opponent in the tumour microenvironment? Nature reviews. Immunology Cancer immunotherapy offers substantive benefit to patients with various tumour types, in some cases leading to complete tumour clearance. However, many patients do not respond to immunotherapy, galvanizing the field to define the mechanisms of pre-existing and acquired resistance. Interferon-γ (IFNγ) is a cytokine that has both protumour and antitumour activities, suggesting that it may serve as a nexus for responsiveness to immunotherapy. Many cancer immunotherapies and chemotherapies induce IFNγ production by various cell types, including activated T cells and natural killer cells. Patients resistant to these therapies commonly have molecular aberrations in the IFNγ signalling pathway or express resistance molecules driven by IFNγ. Given that all nucleated cells can respond to IFNγ, the functional consequences of IFNγ production need to be carefully dissected on a cell-by-cell basis. Here, we review the cells that produce IFNγ and the different effects of IFNγ in the tumour microenvironment, highlighting the pleiotropic nature of this multifunctional and abundant cytokine. 10.1038/s41577-021-00566-3
A timeline of tumour-associated macrophage biology. Nature reviews. Cancer Tumour progression is modulated by the local microenvironment. This environment is populated by many immune cells, of which macrophages are among the most abundant. Clinical correlative data and a plethora of preclinical studies in mouse models of cancers have shown that tumour-associated macrophages (TAMs) play a cancer-promoting role. Within the primary tumour, TAMs promote tumour cell invasion and intravasation and tumour stem cell viability and induce angiogenesis. At the metastatic site, metastasis-associated macrophages promote extravasation, tumour cell survival and persistent growth, as well as maintain tumour cell dormancy in some contexts. In both the primary and metastatic sites, TAMs are suppressive to the activities of cytotoxic T and natural killer cells that have the potential to eradicate tumours. Such activities suggest that TAMs will be a major target for therapeutic intervention. In this Perspective article, we chronologically explore the evolution of our understanding of TAM biology put into the context of major enabling advances in macrophage biology. 10.1038/s41568-022-00547-1
Monocytes in the Tumor Microenvironment. Ugel Stefano,Canè Stefania,De Sanctis Francesco,Bronte Vincenzo Annual review of pathology Immunotherapy has revolutionized cancer treatment over the past decade. Nonetheless, prolonged survival is limited to relatively few patients. Cancers enforce a multifaceted immune-suppressive network whose nature is progressively shaped by systemic and local cues during tumor development. Monocytes bridge innate and adaptive immune responses and can affect the tumor microenvironment through various mechanisms that induce immune tolerance, angiogenesis, and increased dissemination of tumor cells. Yet monocytes can also give rise to antitumor effectors and activate antigen-presenting cells. This yin-yang activity relies on the plasticity of monocytes in response to environmental stimuli. In this review, we summarize current knowledge of the ontogeny, heterogeneity, and functions of monocytes and monocyte-derived cells in cancer, pinpointing the main pathways that are important for modeling the immunosuppressive tumor microenvironment. 10.1146/annurev-pathmechdis-012418-013058
Neutrophil diversity and plasticity in tumour progression and therapy. Jaillon Sebastien,Ponzetta Andrea,Di Mitri Diletta,Santoni Angela,Bonecchi Raffaella,Mantovani Alberto Nature reviews. Cancer Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches. 10.1038/s41568-020-0281-y
Clinical relevance of tumour-associated macrophages. Nature reviews. Clinical oncology In the past decade, substantial advances have been made in understanding the biology of tumour-associated macrophages (TAMs), and their clinical relevance is emerging. A particular aspect that is becoming increasingly clear is that the interaction of TAMs with cancer cells and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. Therefore, manipulation of TAMs could enable improved disease control in a substantial fraction of patients across a large number of cancer types. In this Review, we examine the diversity of TAMs in various cancer indications and how this heterogeneity is being revisited with the advent of single-cell technologies, and then explore the current knowledge on the functional roles of different TAM states and the prognostic and predictive value of TAM-related signatures. We also review agents targeting TAMs that are currently being or will soon be tested in clinical trials, and how manipulations of TAMs can improve existing anticancer treatments. Finally, we discuss how TAM-targeting approaches could be further integrated into routine clinical practice, considering a precision oncology approach and viewing TAMs as a dynamic population that can evolve under treatment pressure. 10.1038/s41571-022-00620-6
Turning foes to friends: targeting cancer-associated fibroblasts. Nature reviews. Drug discovery Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell-cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development. The recent characterization of CAFs based on specific cell surface markers not only deepens our insight into their phenotypic heterogeneity and functional diversity but also brings CAF-targeting therapies for cancer treatment onto the agenda. In this Review, we discuss the current knowledge of biological hallmarks, cellular origins, phenotypical plasticity and functional heterogeneity of CAFs and underscore their contribution to cancer progression. Moreover, we highlight relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment. 10.1038/s41573-018-0004-1
Metabolic programming and immune suppression in the tumor microenvironment. Cancer cell Increased glucose metabolism and uptake are characteristic of many tumors and used clinically to diagnose and monitor cancer progression. In addition to cancer cells, the tumor microenvironment (TME) encompasses a wide range of stromal, innate, and adaptive immune cells. Cooperation and competition between these cell populations supports tumor proliferation, progression, metastasis, and immune evasion. Cellular heterogeneity leads to metabolic heterogeneity because metabolic programs within the tumor are dependent not only on the TME cellular composition but also on cell states, location, and nutrient availability. In addition to driving metabolic plasticity of cancer cells, altered nutrients and signals in the TME can lead to metabolic immune suppression of effector cells and promote regulatory immune cells. Here we discuss how metabolic programming of cells within the TME promotes tumor proliferation, progression, and metastasis. We also discuss how targeting metabolic heterogeneity may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies. 10.1016/j.ccell.2023.01.009
Transcriptome analysis reveals tumor microenvironment changes in glioblastoma. Cancer cell A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells. 10.1016/j.ccell.2023.02.019
Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer cell The mechanisms underlying the multistep process of tumorigenesis can be distilled into a logical framework involving the acquisition of functional capabilities, the so-called hallmarks of cancer, which are collectively envisaged to be necessary for malignancy. These capabilities, embodied both in transformed cancer cells as well as in the heterotypic accessory cells that together constitute the tumor microenvironment (TME), are conveyed by certain abnormal characteristics of the cancerous phenotype. This perspective discusses the link between the nervous system and the induction of hallmark capabilities, revealing neurons and neuronal projections (axons) as hallmark-inducing constituents of the TME. We also discuss the autocrine and paracrine neuronal regulatory circuits aberrantly activated in cancer cells that may constitute a distinctive "enabling" characteristic contributing to the manifestation of hallmark functions and consequent cancer pathogenesis. 10.1016/j.ccell.2023.02.012
The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nature reviews. Clinical oncology Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC. 10.1038/s41571-020-0363-5
Mechanoresponsive metabolism in cancer cell migration and metastasis. Cell metabolism Altered tissue mechanics and metabolism are defining characteristics of cancer that impact not only proliferation but also migration. While migrating through a mechanically and spatially heterogeneous microenvironment, changes in metabolism allow cells to dynamically tune energy generation and bioenergetics in response to fluctuating energy needs. Physical cues from the extracellular matrix influence mechanosignaling pathways, cell mechanics, and cytoskeletal architecture to alter presentation and function of metabolic enzymes. In cancer, altered mechanosensing and metabolic reprogramming supports metabolic plasticity and high energy production while cells migrate and metastasize. Here, we discuss the role of mechanoresponsive metabolism in regulating cell migration and supporting metastasis as well as the potential of therapeutically targeting cancer metabolism to block motility and potentially metastasis. 10.1016/j.cmet.2021.04.002
Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer. Cancer cell Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8 T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target. 10.1016/j.ccell.2022.11.001
Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nature reviews. Cancer Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours. 10.1038/s41568-020-00312-2
The complex role of tumor-infiltrating macrophages. Nature immunology Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being re-discovered as regulators of several diseases, including cancer. Tumor-associated macrophages (TAMs) represent the most abundant innate immune population in the tumor microenvironment (TME). Macrophages are professional phagocytic cells of the hematopoietic system specializing in the detection, phagocytosis and destruction of bacteria and other harmful micro-organisms, apoptotic cells and metabolic byproducts. In contrast to these healthy macrophage functions, TAMs support cancer cell growth and metastasis and mediate immunosuppressive effects on the adaptive immune cells of the TME. Cancer is one of the most potent insults on macrophage physiology, inducing changes that are intimately linked with disease progression. In this Review, we outline hallmarks of TAMs and discuss the emerging mechanisms that contribute to their pathophysiological adaptations and the vulnerabilities that provide attractive targets for therapeutic exploitation in cancer. 10.1038/s41590-022-01267-2
Spatial profiling technologies illuminate the tumor microenvironment. Cancer cell The tumor microenvironment (TME) is composed of many different cellular and acellular components that together drive tumor growth, invasion, metastasis, and response to therapies. Increasing realization of the significance of the TME in cancer biology has shifted cancer research from a cancer-centric model to one that considers the TME as a whole. Recent technological advancements in spatial profiling methodologies provide a systematic view and illuminate the physical localization of the components of the TME. In this review, we provide an overview of major spatial profiling technologies. We present the types of information that can be extracted from these data and describe their applications, findings and challenges in cancer research. Finally, we provide a future perspective of how spatial profiling could be integrated into cancer research to improve patient diagnosis, prognosis, stratification to treatment and development of novel therapeutics. 10.1016/j.ccell.2023.01.010
Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome medicine BACKGROUND:Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. METHODS:We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). RESULTS:Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. CONCLUSIONS:Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance. 10.1186/s13073-023-01164-9
Immune phenotypic linkage between colorectal cancer and liver metastasis. Cancer cell The tumor microenvironment (TME) is connected to immunotherapy responses, but it remains unclear how cancer cells and host tissues differentially influence the immune composition within TME. Here, we performed single-cell analyses for autologous samples from liver metastasized colorectal cancer to disentangle factors shaping TME. By aligning CD45 cells across different tissues, we classified exhausted CD8 T cells (Texs) and activated regulatory T cells as M-type, whose phenotypes were associated with the malignancy, while natural killer and mucosal-associated invariant T cells were defined as N-type, whose phenotypes were associated with the niche. T cell receptor sharing between Texs in primary and metastatic tumors implicated the presence of common peripheral non-exhausted precursors. For myeloid cells, a subset of dendritic cells (DC3s) and SPP1 macrophages were M-type, and the latter were predominant in liver metastasis, indicating its pro-metastasis role. Our analyses bridge immune phenotypes of primary and metastatic tumors, thereby helping to understand the tumor-specific contexture and identify the pro-metastasis components. 10.1016/j.ccell.2022.02.013
Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer. Cancer discovery Gastric cancer heterogeneity represents a barrier to disease management. We generated a comprehensive single-cell atlas of gastric cancer (>200,000 cells) comprising 48 samples from 31 patients across clinical stages and histologic subtypes. We identified 34 distinct cell-lineage states including novel rare cell populations. Many lineage states exhibited distinct cancer-associated expression profiles, individually contributing to a combined tumor-wide molecular collage. We observed increased plasma cell proportions in diffuse-type tumors associated with epithelial-resident KLF2 and stage-wise accrual of cancer-associated fibroblast subpopulations marked by high INHBA and FAP coexpression. Single-cell comparisons between patient-derived organoids (PDO) and primary tumors highlighted inter- and intralineage similarities and differences, demarcating molecular boundaries of PDOs as experimental models. We complemented these findings by spatial transcriptomics, orthogonal validation in independent bulk RNA-sequencing cohorts, and functional demonstration using in vitro and in vivo models. Our results provide a high-resolution molecular resource of intra- and interpatient lineage states across distinct gastric cancer subtypes. SIGNIFICANCE:We profiled gastric malignancies at single-cell resolution and identified increased plasma cell proportions as a novel feature of diffuse-type tumors. We also uncovered distinct cancer-associated fibroblast subtypes with INHBA-FAP-high cell populations as predictors of poor clinical prognosis. Our findings highlight potential origins of deregulated cell states in the gastric tumor ecosystem. This article is highlighted in the In This Issue feature, p. 587. 10.1158/2159-8290.CD-21-0683
Harnessing cytokines and chemokines for cancer therapy. Nature reviews. Clinical oncology During the past 40 years, cytokines and cytokine receptors have been extensively investigated as either cancer targets or cancer treatments. A strong preclinical rationale supports therapeutic strategies to enhance the growth inhibitory and immunostimulatory effects of interferons and interleukins, including IL-2, IL-7, IL-12 and IL-15, or to inhibit the inflammatory and tumour-promoting actions of cytokines such as TNF, IL-1β and IL-6. This rationale is underscored by the discovery of altered and dysregulated cytokine expression in all human cancers. These findings prompted clinical trials of several cytokines or cytokine antagonists, revealing relevant biological activity but limited therapeutic efficacy. However, most trials involved patients with advanced-stage disease, which might not be the optimal setting for cytokine-based therapy. The advent of more effective immunotherapies and an increased understanding of the tumour microenvironment have presented new approaches to harnessing cytokine networks in the treatment of cancer, which include using cytokine-based therapies to enhance the activity or alleviate the immune-related toxicities of other treatments as well as to target early stage cancers. Many challenges remain, especially concerning delivery methods, context dependencies, and the pleiotropic, redundant and often conflicting actions of many cytokines. Herein, we discuss the lessons learnt from the initial trials of single-agent cytokine-based therapies and subsequent efforts to better exploit such agents for the treatment of solid tumours. 10.1038/s41571-021-00588-9
Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. Annual review of pathology Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. Recent advances in tissue imaging capabilities, single-cell analytics, and disease modeling have shed light on organizing principles that shape the stromal complexity of PDAC tumors. These insights into the functional and spatial dependencies that coordinate cancer cell biology and the relationships that exist between cells and extracellular matrix components present in tumors are expected to unveil therapeutic vulnerabilities. We review recent advances in the field and discuss current understandings of mechanisms by which the tumor microenvironment shapes PDAC pathogenesis and therapy resistance. 10.1146/annurev-pathmechdis-031621-024600
Pathogenesis of Triple-Negative Breast Cancer. Annual review of pathology Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles, which are aggregated under this term because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Massively parallel sequencing and other omics technologies have demonstrated the level of heterogeneity in TNBCs and shed light into the pathogenesis of this therapeutically challenging entity in breast cancer. In this review, we discuss the histologic and molecular classifications of TNBC, the genomic alterations these different tumor types harbor, and the potential impact of these alterations on the pathogenesis of these tumors. We also explore the role of the tumor microenvironment in the biology of TNBCs and its potential impact on therapeutic response. Dissecting the biology and understanding the therapeutic dependencies of each TNBC subtype will be essential to delivering on the promise of precision medicine for patients with triple-negative disease. 10.1146/annurev-pathol-042420-093238
Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nature genetics Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis. 10.1038/s41588-022-01141-9
Hallmarks of Cancer: New Dimensions. Hanahan Douglas Cancer discovery The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine. 10.1158/2159-8290.CD-21-1059
The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer cell Cancers represent complex ecosystems comprising tumor cells and a multitude of non-cancerous cells, embedded in an altered extracellular matrix. The tumor microenvironment (TME) includes diverse immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and various additional tissue-resident cell types. These host cells were once considered bystanders of tumorigenesis but are now known to play critical roles in the pathogenesis of cancer. The cellular composition and functional state of the TME can differ extensively depending on the organ in which the tumor arises, the intrinsic features of cancer cells, the tumor stage, and patient characteristics. Here, we review the importance of the TME in each stage of cancer progression, from tumor initiation, progression, invasion, and intravasation to metastatic dissemination and outgrowth. Understanding the complex interplay between tumor cell-intrinsic, cell-extrinsic, and systemic mediators of disease progression is critical for the rational development of effective anti-cancer treatments. 10.1016/j.ccell.2023.02.016