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- Volume 4, 2020
Annual Review of Cancer Biology - Volume 4, 2020
Volume 4, 2020
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AMP-Activated Protein Kinase: Friend or Foe in Cancer?
Vol. 4 (2020), pp. 1–16More LessThe AMP-activated protein kinase (AMPK) is activated by energy stress and restores homeostasis by switching on catabolism, while switching off cell growth and proliferation. Findings that AMPK acts downstream of the tumor suppressor LKB1 have suggested that AMPK might also suppress tumorigenesis. In mouse models of B and T cell lymphoma in which genetic loss of AMPK occurred before tumor initiation, tumorigenesis was accelerated, confirming that AMPK has tumor-suppressor functions. However, when loss of AMPK in a T cell lymphoma model occurred after tumor initiation, or simultaneously with tumor initiation in a lung cancer model, the disease was ameliorated. Thus, once tumorigenesis has occurred, AMPK switches from tumor suppression to tumor promotion. Analysis of alterations in AMPK genes in human cancers suggests similar dichotomies, with some genes being frequently amplified while others are mutated. Overall, while AMPK-activating drugs might be effective in preventing cancer, in some cases AMPK inhibitors might be required to treat it.
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Metabolism in the Tumor Microenvironment
Vol. 4 (2020), pp. 17–40More LessExperiments in culture systems where one cell type is provided with abundant nutrients and oxygen have been used to inform much of our understanding of cancer metabolism. However, many differences have been observed between the metabolism of tumors and the metabolism of cancer cells grown in monoculture. These differences reflect, at least in part, the presence of nonmalignant cells in the tumor microenvironment and the interactions between those cells and cancer cells. However, less is known about how the metabolism of various tumor stromal cell types differs from that of cancer cells, and how this difference might inform therapeutic targeting of metabolic pathways. Emerging data have identified both cooperative and competitive relationships between different cell types in a tumor, and this review examines how four abundant stromal cell types in the tumor microenvironment, fibroblasts, T cells, macrophages, and endothelial cells, contribute to the metabolism of tumors.
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Mitophagy and Mitochondrial Dysfunction in Cancer
Vol. 4 (2020), pp. 41–60More LessThe process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to key physiological stresses, such as hypoxia, nutrient deprivation, and DNA damage. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Consequently, functional mitophagy contributes to proper tissue differentiation and repair and metabolic homeostasis, limiting inflammatory responses and modulating tumor progression and metastasis. This review examines the major pathways that control mitophagy, including PINK1-dependent mitophagy and BNIP3/NIX-dependent mitophagy. It also discusses the cellular signaling mechanisms used to sense mitochondrial dysfunction to activate mitophagy and how defective mitophagy results in deregulated tumor cell growth and cancer.
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Targeting MYC Proteins for Tumor Therapy
Elmar Wolf, and Martin EilersVol. 4 (2020), pp. 61–75More LessTargeting the function of MYC oncoproteins holds the promise of achieving conceptually new and effective anticancer therapies that can be applied to a broad range of tumors. The nature of the target however—a broadly, possibly universally acting transcription factor that has no enzymatic activity and is largely unstructured unless complexed with partner proteins—has so far defied the development of clinically applicable MYC-directed therapies. At the same time, lingering questions about exactly which functions of MYC proteins account for their pervasive oncogenic role in human tumors and need to be targeted have prevented the development of effective therapies using surrogate targets that act in critical MYC-dependent pathways. In this review, we therefore argue that rigorous testing of critical oncogenic functions and protein/protein interactions and new chemical approaches to target them are necessary to successfully eradicate MYC-driven tumors.
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Metabolic Drivers in Hereditary Cancer Syndromes
Vol. 4 (2020), pp. 77–97More LessCancer is a multifaceted disease in which inherited genetic variants can be important drivers of tumorigenesis. The discovery that germline mutations of metabolic genes predispose to familial forms of cancer caused a shift in our understanding of how metabolism contributes to tumorigenesis, providing evidence that metabolic alterations can be oncogenic. In this review, we focus on mitochondrial enzymes whose mutations predispose to familial cancer, and we fully appraise their involvement in cancer formation and progression. Elucidating the molecular mechanisms that orchestrate transformation in these diverse tumors may answer key biological questions about tumor formation and evolution, leading to the identification of new therapeutic targets of intervention.
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Investigating Tumor Heterogeneity in Mouse Models
Vol. 4 (2020), pp. 99–119More LessCancer arises from a single cell through a series of acquired mutations and epigenetic alterations. Tumors gradually develop into a complex tissue comprised of phenotypically heterogeneous cancer cell populations, as well as noncancer cells that make up the tumor microenvironment. The phenotype, or state, of each cancer and stromal cell is influenced by a plethora of cell-intrinsic and cell-extrinsic factors. The diversity of these cellular states promotes tumor progression, enables metastasis, and poses a challenge for effective cancer treatments. Thus, the identification of strategies for the therapeutic manipulation of tumor heterogeneity would have significant clinical implications. A major barrier in the field is the difficulty in functionally investigating heterogeneity in tumors in cancer patients. Here we review how mouse models of human cancer can be leveraged to interrogate tumor heterogeneity and to help design better therapeutic strategies.
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Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology
Vol. 4 (2020), pp. 121–139More LessT cells engineered to recognize and kill tumor cells have emerged as powerful agents for combating cancer. Nonetheless, our ability to engineer T cells remains relatively primitive. Aside from CAR T cells for treating B cell malignancies, most T cell therapies are risky, toxic, and often ineffective, especially those that target solid cancers. To fulfill the promise of cell-based therapies, we must transform cell engineering into a systematic and predictable science by applying the principles and tools of synthetic biology. Synthetic biology uses a hierarchical approach—assembling sets of modular molecular parts that can be combined into larger circuits and systems that perform defined target tasks. We outline the toolkit of synthetic modules that are needed to overcome the challenges of solid cancers, progress in building these components, and how these modules could be used to reliably engineer more effective and precise T cell therapies.
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Lactate and Acidity in the Cancer Microenvironment
Vol. 4 (2020), pp. 141–158More LessFermentative glycolysis, an ancient evolved metabolic pathway, is exploited by rapidly growing tissues and tumors but also occurs in response to the nutritional and energetic demands of differentiated tissues. The lactic acid it produces is transported across cell membranes through reversible H+/lactate− symporters (MCT1 and MCT4) and is recycled in organs as a major metabolic precursor of gluconeogenesis and an energy source. Concentrations of lactate in the tumor environment, investigated utilizing an induced metabolic bioluminescence imaging (imBI) technique, appear to be dominant biomarkers of tumor response to irradiation and resistance to treatment. Suppression of lactic acid formation by genetic disruption of lactate dehydrogenases A and B in aggressive tumors reactivated OXPHOS (oxidative phosphorylation) to maintain xenograft tumor growth at a halved rate. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Furthermore, the global reduction of tumor acidity contributes to activation of the antitumor immune responses, offering hope for future clinical applications.
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Reactivation of Endogenous Retroelements in Cancer Development and Therapy
Vol. 4 (2020), pp. 159–176More LessDomesticated retroelements contribute extensively as regulatory elements within host gene networks. Upon germline integration, retroelement mobilization is restricted through epigenetic silencing, mutational degradation, and innate immune defenses described as the viral mimicry response. Recent discoveries reveal how early events in tumorigenesis reactivate retroelements to facilitate onco-exaptation, replication stress, retrotransposition, mitotic errors, and sterile inflammation, which collectively disrupt genome integrity. The characterization of altered epigenetic homeostasis at retroelements in cancer cells also reveals new epigenetic targets whose inactivation can bolster responses to cancer therapies. Recent discoveries reviewed here frame reactivated retroelements as both drivers of tumorigenesis and therapy responses, where their reactivation by emerging epigenetic therapies can potentiate immune checkpoint blockade, cancer vaccines, and other standard therapies.
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WNT and β-Catenin in Cancer: Genes and Therapy
Vol. 4 (2020), pp. 177–196More LessThe WNT pathway is a pleiotropic signaling pathway that controls developmental processes, tissue homeostasis, and cancer. The WNT pathway is commonly mutated in many cancers, leading to widespread research into the role of WNT signaling in carcinogenesis. Understanding which cancers are reliant upon WNT activation and which components of the WNT signaling pathway are mutated is paramount to advancing therapeutic strategies. In addition, building holistic insights into the role of WNT signaling in not only tumor cells but also the tumor microenvironment is a vital area of research and may be a promising therapeutic strategy in multiple immunologically inert cancers. Novel compounds aimed at modulating the WNT signaling pathway using diverse mechanisms are currently under investigation in preclinical/early clinical studies. Here, we review how the WNT pathway is activated in multiple cancers and discuss current strategies to target aberrant WNT signaling.
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The Epithelial-to-Mesenchymal Transition in Development and Cancer
Vol. 4 (2020), pp. 197–220More LessEpithelial-to-mesenchymal transitions (EMTs) are complex cellular processes where cells undergo dramatic changes in signaling, transcriptional programming, and cell shape, while directing the exit of cells from the epithelium and promoting migratory properties of the resulting mesenchyme. EMTs are essential for morphogenesis during development and are also a critical step in cancer progression and metastasis formation. Here we provide an overview of the molecular regulation of the EMT process during embryo development, focusing on chick and mouse gastrulation and neural crest development. We go on to describe how EMT regulators participate in the progression of pancreatic and breast cancer in mouse models, and discuss the parallels with developmental EMTs and how these help to understand cancer EMTs. We also highlight the differences between EMTs in tumor and in development to arrive at a broader view of cancer EMT. We conclude by discussing how further advances in the field will rely on in vivo dynamic imaging of the cellular events of EMT.
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RNA Modifications in Cancer: Functions, Mechanisms, and Therapeutic Implications
Vol. 4 (2020), pp. 221–240More LessOver 170 chemical modifications have been identified in protein-coding and noncoding RNAs and shown to exhibit broad impacts on gene expression. Dysregulation of RNA modifications caused by aberrant expression of or mutations in RNA modifiers aberrantly reprograms the epitranscriptome and skews global gene expression, which in turn leads to tumorigenesis and drug resistance. Here we review current knowledge of the functions and underlying mechanisms of aberrant RNA modifications in human cancers, particularly several common RNA modifications, including N6-methyladenosine (m6A), A-to-I editing, pseudouridine (ψ), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), N1-methyladenosine (m1A), and N4-acetylcytidine (ac4C), providing insights into therapeutic implications of targeting RNA modifications and the associated machineries for cancer therapy.
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Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma?
Vol. 4 (2020), pp. 241–256More LessIndoleamine-2,3 dioxygenase 1 (IDO1) contributes to tumor immunosuppression by enzymatically degrading tryptophan, which is required for T cell activity, and producing kynurenine. Small-molecule inhibitors, such as epacadostat, have been developed to block IDO1 activity. In preclinical models, they can restore antitumoral T cell immunity and synergize with immune checkpoint inhibitors or cancer vaccines. Based on encouraging clinical results in early phase trials, a randomized phase III study (ECHO-301/KN-252) was launched in metastatic melanoma to test the benefit of adding epacadostat to the reference pembrolizumab therapy. The result was negative. We briefly review the clinical trials that investigated epacadostat in cancer patients and discuss possible explanations for this negative result. We end by suggesting paths to resume clinical development of compounds targeting the IDO1 pathway, which in our view remains an attractive target for cancer immunotherapy.
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Deregulation of Chromosome Segregation and Cancer
Vol. 4 (2020), pp. 257–278More LessThe mitotic spindle assembly checkpoint (SAC) is an intricate cell signaling system that ensures the high fidelity and timely segregation of chromosomes during cell division. Mistakes in this process can lead to the loss, gain, or rearrangement of the genetic material. Gross chromosomal aberrations are usually lethal but can cause birth and development defects as well as cancer. Despite advances in the identification of SAC protein components, important details of the interactions underpinning chromosome segregation regulation remain to be established. This review discusses the current understanding of the function, structure, mode of regulation, and dynamics of the assembly and disassembly of SAC subcomplexes, which ultimately safeguard the accurate transmission of a stable genome to descendants. We also discuss how diverse oncoviruses take control of human cell division by exploiting the SAC and the potential of this signaling circuitry as a pool of drug targets to develop effective cancer therapies.
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Acquired Resistance in Lung Cancer
Vol. 4 (2020), pp. 279–297More LessThe last decade has witnessed a transformation in the treatment of advanced-stage lung cancer from a largely palliative approach to one where long-term durable remissions and even cures might be within reach. In this review, we discuss the current state of oncogene-directed precision medicine therapies in lung cancer and focus on the major cause of mortality for lung cancer patients: acquired resistance. We consider the multifaceted resistance mechanisms tumors utilize, often simultaneously. We then present areas for future scientific and clinical investigation with an emphasis on population dynamics, early detection, combinatorial therapies targeting resistance mechanisms, and understanding the drug-tolerant persister state.
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Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy
Vol. 4 (2020), pp. 299–313More LessApoptosis is critical for embryonic development, tissue homeostasis, and the removal of infected or otherwise dangerous cells. It is controlled by three subgroups of the BCL-2 protein family—the BH3-only proteins that initiate cell death; the effectors of cell killing, BAX and BAK; and the antiapoptotic guardians, including MCL-1 and BCL-2. Defects in apoptosis can promote tumorigenesis and render malignant cells refractory to anticancer therapeutics. Activation of cell death by inhibiting antiapoptotic BCL-2 family members has emerged as an attractive strategy for cancer therapy, with the BCL-2 inhibitor venetoclax leading the way. Large-scale cancer genome analyses have revealed frequent amplification of the locus encoding antiapoptotic MCL-1 in human cancers, and functional studies have shown that MCL-1 is essential for the sustained survival and expansion of many types of tumor cells. Structural analysis and medicinal chemistry have led to the development of three distinct small-molecule inhibitors of MCL-1 that are currently undergoing clinical testing.
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Nongenetic Mechanisms of Drug Resistance in Melanoma
Vol. 4 (2020), pp. 315–330More LessResistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.
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Biomarkers for Response to Immune Checkpoint Blockade
Vol. 4 (2020), pp. 331–351More LessImmune checkpoint blockade (ICB) has significant clinical activity in diverse cancer classes and can induce durable remissions in even refractory advanced disease. However, only a minority of cancer patients treated with ICB have long-term benefits, and ICB treatment is associated with significant, potentially life-threatening, autoimmune side effects. There is a great need to develop biomarkers of response to guide patient selection to maximize the chance of benefit and prevent unnecessary toxicity, and current biomarkers do not have optimal positive or negative predictive value. A variety of potential biomarkers are currently being developed, including those based on assessment of checkpoint protein expression, evaluation of tumor-intrinsic features including mutation burden and viral infection, evaluation of features of the tumor immune microenvironment including nature of immune cell infiltration, and features of the host such as composition of the gut microbiome. Better understanding of the underlying fundamental mechanisms of immune response and resistance to ICB, along with the use of complementary assays that interrogate distinct features of the tumor, the tumor microenvironment, and host immune system, will allow more precise use of these therapies to optimize patient outcomes.
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Immune-Based Approaches for the Treatment of Pediatric Malignancies
Vol. 4 (2020), pp. 353–370More LessImmune-based therapies have now been credentialed for pediatric cancers with the robust efficacy of chimeric antigen receptor (CAR) T cells for pediatric B cell acute lymphocytic leukemia (ALL), offering a chance of a cure for children with previously lethal disease and a potentially more targeted therapy to limit treatment-related morbidities. The developmental origins of most pediatric cancers make them ideal targets for immune-based therapies that capitalize on the differential expression of lineage-specific cell surface molecules such as antibodies, antibody-drug conjugates, or CAR T cells, while the efficacy of other therapies that depend on tumor immunogenicity such as immune checkpoint inhibitors has been limited to date. Here we review the current status of immune-based therapies for childhood cancers, discuss challenges to developing immunotherapeutics for these diseases, and outline future directions of pediatric immunotherapy discovery and development.
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The Neural Regulation of Cancer
Vol. 4 (2020), pp. 371–390More LessThe nervous system is intimately involved in physiological processes from development and growth to tissue homeostasis and repair throughout the body. It logically follows that the nervous system has the potential to play analogous roles in the context of cancer. Progress toward understanding the crucial role of the nervous system in cancer has accelerated in recent years, but much remains to be learned. Here, we highlight rapidly evolving concepts in this burgeoning research space and consider next steps toward understanding and therapeutically targeting the neural regulation of cancer.
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