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Annual Review of Cancer Biology - Volume 5, 2021
Volume 5, 2021
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Zena Werb (1945–2020): Matrix Metalloproteinases, Microenvironments, and Mentoring
Vol. 5 (2021), pp. 1–16More LessOn June 16, 2020, Zena Werb, PhD, died suddenly at age 75. Zena was a faculty member of the Department of Anatomy at the University of California, San Francisco (UCSF) for over 40 years. She was one of the most cited scientists in the life sciences, with an H-index of 170. She was well known for discovering several matrix metalloproteinases and for defining their roles in development and disease. Zena Werb was a major contributor to the recent appreciation—and deeper understanding—of the importance of the tumor microenvironment. She achieved this by her scientific discoveries, by being a thought leader—responsible for several influential reviews in the field—and by mentoring several generations of researchers in the tumor microenvironment field.
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Myeloid-Derived Suppressor Cells: Facilitators of Cancer and Obesity-Induced Cancer
Vol. 5 (2021), pp. 17–38More LessImmature myeloid cells at varied stages of differentiation, known as myeloid-derived suppressor cells (MDSC), are present in virtually all cancer patients. MDSC are profoundly immune-suppressive cells that impair adaptive and innate antitumor immunity and promote tumor progression through nonimmune mechanisms. Their widespread presence combined with their multitude of protumor activities makes MDSC a major obstacle to cancer immunotherapies. MDSC are derived from progenitor cells in the bone marrow and traffic through the blood to infiltrate solid tumors. Their accumulation and suppressive potency are driven by multiple tumor- and host-secreted proinflammatory factors and adrenergic signals that act via diverse but sometimes overlapping transcriptional pathways. MDSC also accumulate in response to the chronic inflammation and lipid deposition characteristic of obesity and contribute to the more rapid progression of cancers in obese individuals. This article summarizes the key aspects of tumor-induced MDSC with a focus on recent progress in the MDSC field.
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Ex Vivo Analysis of Primary Tumor Specimens for Evaluation of Cancer Therapeutics
Vol. 5 (2021), pp. 39–57More LessThe use of ex vivo drug sensitivity testing to predict drug activity in individual patients has been actively explored for almost 50 years without delivering a generally useful predictive capability. However, extended failure should not be an indicator of futility. This is especially true in cancer research, where ultimate success is often preceded by less successful attempts. For example, both immune- and genetic-based targeted therapies for cancer underwent numerous failed attempts before biological understanding, improved targets, and optimized drug development matured to facilitate an arsenal of transformational drugs. Similarly, directly assessing drug sensitivity of primary tumor biopsies—and the use of this information to help direct therapeutic approaches—has a long history with a definitive learningcurve. In this review, we survey the history of ex vivo testing and the current state of the art for this field. We present an update on methodologies and approaches, describe the use of these technologies to test cutting-edge drug classes, and describe an increasingly nuanced understanding of tumor types and models for which this strategy is most likely to succeed. We consider the relative strengths and weaknesses of predicting drug activity across the broad biological context of cancer patients and tumor types. This includes an analysis of the potential for ex vivo drug sensitivity testing to accurately predict drug activity within each of the biological hallmarks of cancer pathogenesis.
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Telomeres and Cancer: Resolving the Paradox
Vol. 5 (2021), pp. 59–77More LessDecades of study on cell cycle regulation have provided great insight into human cellular life span barriers, as well as their dysregulation during tumorigenesis. Telomeres, the extremities of linear chromosomes, perform an essential role in implementing these proliferative boundaries and preventing the propagation of potentially cancerous cells. The tumor-suppressive function of telomeres relies on their ability to initiate DNA damage signaling pathways and downstream cellular events, ranging from cell cycle perturbation to inflammation and cell death. While the tumor-suppressor role of telomeres is undoubtable, recent advances have pointed to telomeres as a major source of many of the genomic aberrations found in both early- and late-stage cancers, including the most recently discovered mutational phenomenon of chromothripsis. Telomere shortening appears as a double-edged sword that can function in opposing directions in carcinogenesis. This review focuses on the current knowledge of the dual role of telomeres in cancer and suggests a new perspective to reconcile the paradox of telomeres and their implications in cancer etiology.
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Molecular Heterogeneity and Evolution in Breast Cancer
Vol. 5 (2021), pp. 79–94More LessBreast cancer comprises a heterogeneous group of tumor subtypes, whether defined by immunohistochemistry of key proteins, RNA expression profiles, or genetic alterations, and each of these subtypes may benefit from a distinct treatment approach. However, there can be striking heterogeneity within tumors, which may pose challenges to the development of personalized approaches to therapy. Intratumor heterogeneity can be divided into three main categories: genetic, phenotypic, and microenvironmental. Here, we review technologies to interrogate these three categories of heterogeneity in patient samples, as well as the current state of understanding of these categories in breast cancer, from cell to cell, across different regions of the same tumor mass, across treatment, and across metastasis. Efforts to characterize tumor heterogeneity longitudinally will be crucial to the development of personalized oncology for breast cancer.
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Molecular Biology of Childhood Leukemia
Vol. 5 (2021), pp. 95–117More LessChildhood hematological malignancies (HM) exhibit profound genetic and biological heterogeneity. Many sporadic and familial HM have a heritable predisposition. Genomic sequencing has revised the taxonomy of lymphoid and myeloid leukemias, indicating the importance of accurate molecular diagnosis in disease management. Notable examples include the identification of gene expression–based subtypes of acute lymphoblastic leukemia (ALL), identification of diverse rearrangements of NUP98 in high-risk acute myeloid leukemia (AML), characterization of the interplay of cell-of-origin and genomic alterations in lineage-ambiguous leukemias, and the prognostic importance of DNA methylation in juvenile myelomonocytic leukemias. These insights provide therapeutic opportunities, including kinase inhibition in Ph-like ALL, menin inhibition in KMT2A-rearranged AML, histone deacetylase inhibition in MEF2D-rearranged ALL, and FLT3 inhibition in T-lineage and myeloid leukemias. We provide an overview of the molecular foundation and classification of childhood leukemias, focusing on recent scientific advances, and discuss potential therapeutic implications.
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Humanized Mouse Models to Evaluate Cancer Immunotherapeutics
Vol. 5 (2021), pp. 119–136More LessImmunotherapy is at the forefront of cancer treatment. The advent of numerous novel approaches to cancer immunotherapy, including immune checkpoint antibodies, adoptive transfer of CAR (chimeric antigen receptor) T cells and TCR (T cell receptor) T cells, NK (natural killer) cells, T cell engagers, oncolytic viruses, and vaccines, is revolutionizing the treatment for different tumor types. Some are already in the clinic, and many others are underway. However, not all patients respond, resistance develops, and as available therapies multiply there is a need to further understand how they work, how to prioritize their clinical evaluation, and how to combine them. For this, animal models have been highly instrumental, and humanized mice models (i.e., immunodeficient mice engrafted with human immune and cancer cells) represent a step forward, although they have several limitations. Here, we review the different humanized models available today, the approaches to overcome their flaws, their use for the evaluation of cancer immunotherapies, and their anticipated evolution as tools to help personalized clinical decision-making.
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Immunometabolism in the Tumor Microenvironment
Vol. 5 (2021), pp. 137–159More LessAdvances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells are shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity.
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Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging
Vol. 5 (2021), pp. 161–179More LessDietary restriction (DR) is the most successful nutritional intervention for extending lifespan and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life- and health span and decrease DNA damage in DNA repair–deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment.
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Small-Molecule Approaches to Targeted Protein Degradation
Vol. 5 (2021), pp. 181–201More LessMany essential biological processes are regulated through proximity, from membrane receptor signaling to transcriptional activity. The ubiquitin-proteasome system controls protein degradation, with ubiquitin ligases as the rate-limiting step. Ubiquitin ligases are commonly controlled at the level of substrate recruitment and, therefore, by proximity. There are natural and synthetic small molecules that also operate through induced proximity. For example, thalidomide is effective in treating multiple myeloma and functions as a molecular glue that stabilizes novel protein-protein interactions between a ubiquitin ligase and proteins not otherwise targeted by the ligase, leading to neo-substrate degradation. Emerging data on new degrader molecules have uncovered diverse mechanisms distinct from molecular glues, which often mirror the regulatory mechanisms that control substrate-ligase proximity in nature. In this review, we summarize our current understanding of biological and synthetic regulation of protein degradation and share our view on how these diverse mechanisms have inspired novel therapeutic directions.
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Cancer Immunotherapy and the Nectin Family
Vol. 5 (2021), pp. 203–219More LessIt is increasingly clear that the nectin family and its immunoreceptors shape the immune response to cancer through several pathways. Yet, even as antibodies against TIGIT, CD96, and CD112R advance into clinical development, biological and therapeutic questions remain unanswered. Here, we review recent progress, prospects, and challenges to understanding and tapping this family in cancer immunotherapy.
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Mutant Allele Imbalance in Cancer
Vol. 5 (2021), pp. 221–234More LessThe search for somatic mutations that drive the initiation and progression of human tumors has dominated recent cancer research. While much emphasis has been placed on characterizing the prevalence and function of driver mutations, comparatively less is known about their serial genetic evolution. Indeed, study of this phenomenon has largely focused on tumor-suppressor genes recessive at the cellular level or mechanisms of resistance in tumors with mutant oncogenes targeted by therapy. There is, however, a growing appreciation that despite a decades-old presumption of heterozygosity, changes in mutant oncogene zygosity are common and drive dosage and stoichiometry changes that lead to selective growth advantages. Here, we review the recent progress in understanding mutant allele imbalance and its implications for tumor biology, cancer evolution, and response to anticancer therapy.
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The Bidirectional Relationship Between Cancer Epigenetics and Metabolism
Vol. 5 (2021), pp. 235–257More LessMetabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.
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Personal Neoantigen Vaccines for the Treatment of Cancer
Vol. 5 (2021), pp. 259–276More LessCancer vaccines can generate and amplify tumor-specific T cell responses with the promise to provide long-term control of cancer. All cancer cells harbor genetic alterations encoding neoantigens that are specific to the tumor and not present in normal tissue. Similar to foreign antigens targeted by T cells in infectious disease settings, neoantigens represent the long elusive immunogens for cancer vaccination. Since the vast majority of mutations are unique to individual tumors, neoantigen vaccines require custom design for each patient. The availability of rapid and cost-effective genome sequencing, along with advanced bioinformatics tools, now allows neoantigen-target discovery and vaccine manufacturing in sufficient time for the treatment of cancer patients. Clinical trials in melanoma and glioblastoma have demonstrated the feasibility, immunogenicity, and signals of efficacy of this personalized immunotherapy approach. Key unresolved areas include identification of the most effective vaccine delivery platforms, validation and consensus of neoantigen target selection, and optimal strategies for partnering immunotherapies. Given the universal presence of mutations in cancer and the patient-tailored paradigm, personalized neoantigen vaccines have potential applicability for all cancer patients.
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The Intriguing Clinical Success of BCL-2 Inhibition in Acute Myeloid Leukemia
Vol. 5 (2021), pp. 277–289More LessOver the past several decades numerous preclinical and clinical studies have pursued new approaches for the treatment of acute myeloid leukemia (AML). While some degree of clinical response has been demonstrated for many therapies, for the most part, fundamental changes in the treatment landscape have been lacking. Recently, the use of the BCL-2 inhibitor venetoclax has emerged as a potent therapy for a majority of newly diagnosed AML patients. Venetoclax regimens have shown broad response rates with deep and durable remissions, with a superior toxicity profile compared with traditional intensive chemotherapy agents. Numerous ongoing studies are now using venetoclax in combination with a wide range of other agents as investigators seek even more effective and well-tolerated regimens. Notably, however, while the empirical results of BCL-2 inhibition are encouraging, the mechanisms that have led to these successful clinical outcomes remain unclear. Intriguingly, the activity of venetoclax in AML patients appears to go beyond simply modulating canonical antiapoptosis mechanisms; in addition, the efficacy of venetoclax is linked to its combined use with conventional low-intensity backbone therapies. This article will evaluate the state of the field, provide a summary of key considerations, and propose directions for future studies.
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The Multifaceted Role of Regulatory T Cells in Breast Cancer
Vol. 5 (2021), pp. 291–310More LessThe microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (Tregs), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral Tregs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that Tregs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, Tregs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into Treg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies.
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The Role of Epigenetic Mechanisms in B Cell Lymphoma Pathogenesis
Vol. 5 (2021), pp. 311–330More LessThe capacity of the adaptive immune system to respond to antigenic challenges relies on rapid diversification, expansion, and functional specialization of mature B cells. To accomplish this, activated B cells are transiently endowed with phenotypes that would normally be suppressed in somatic cells, such as enhanced proliferative potential and tolerance for genomic instability. Acquisition of these traits, directed by immune signaling cues and orchestrated by transcriptional and epigenetic programs, sets the stage for malignant transformation, often due to somatic mutations targeting epigenetic machinery in B cell lymphomas. This review examines how such mutations hack the epigenome to reprogram the immune response in such a way as to facilitate the emergence of malignant traits, suppress immune surveillance, and ultimately drive transformation and progression of a diverse spectrum of B cell lymphomas. Importantly, these novel mechanisms reveal vulnerabilities that can be harnessed using new forms of epigenetic therapy.
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Reeling in the Zebrafish Cancer Models
Vol. 5 (2021), pp. 331–350More LessZebrafish are rapidly becoming a leading model organism for cancer research. The genetic pathways driving cancer are highly conserved between zebrafish and humans, and the ability to easily manipulate the zebrafish genome to rapidly generate transgenic animals makes zebrafish an excellent model organism. Transgenic zebrafish containing complex, patient-relevant genotypes have been used to model many cancer types. Here we present a comprehensive review of transgenic zebrafish cancer models as a resource to the field and highlight important areas of cancer biology that have yet to be studied in the fish. The ability to image cancer cells and niche biology in an endogenous tumor makes zebrafish an indispensable model organism in which we can further understand the mechanisms that drive tumorigenesis and screen for potential new cancer therapies.
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Developmental Insights into Lung Cancer
Vol. 5 (2021), pp. 351–369More LessLung cancer continues to be the number one cancer killer. Despite a surge of therapeutic advances in recent years, lung cancer remains fatal when it presents at a stage too advanced for surgical resection. In part, this is due to the disappointing reality of inevitable drug resistance in the face of highly effective, mutation-specific chemotherapy and the limited efficacy of immune checkpoint blockade. Yet, with the increasing application and integration of diverse genomic profiling approaches and the advent of high-content single-cell technologies, the mechanisms of lung cancer initiation, evolution, spread, and resistance are being unraveled at unprecedented resolution. Increasingly sophisticated mouse genetic, xenotransplantation, and ex vivo assays are also enabling functional validation and empiric screening of new therapeutic candidates. In this review, I highlight recent insights into the genetic, cellular, and molecular mechanisms of lung cancer and relate them to the normal biology of the developing and mature lung.
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Cancer Dependencies: PRMT5 and MAT2A in MTAP/p16-Deleted Cancers
Vol. 5 (2021), pp. 371–390More LessDiscovery of targeted therapies that selectively exploit the genetic inactivation of specific tumor suppressors remains a major challenge. This includes the prevalent deletion of the CDKN2A/MTAP locus, which was first reported nearly 40 years ago. The more recent advent of RNA interference and functional genomic screening technologies led to the identification of hidden collateral lethalities occurring with passenger deletions of MTAP in cancer cells. In particular, small-molecule inhibition of the type II arginine methyltransferase PRMT5 and the S-adenosylmethionine-producing enzyme MAT2A each presents a precision medicine approach for the treatment of patients whose tumors have homozygous loss of MTAP. In this review, we highlight key aspects of MTAP, PRMT5, and MAT2A biology to provide a conceptual framework for developing novel therapeutic strategies in tumors with MTAP deletion and to summarize ongoing efforts to drug PRMT5 and MAT2A.
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