Annual Review of Cancer Biology - Volume 2, 2018

Scientific discoveries spring not only from intellect, intuition, and persistent effort but also from unforeseen circumstances, accidental observations, and chance interpersonal encounters. Unanticipated detours from intended career paths can nurture an inclination to shift one's focus and take on risk, providing the freedom to explore uncharted avenues. Here I recount some early events that transformed the directions of my own research.

Cancer arises from genetic alterations that produce dysregulated gene expression programs. Normal gene regulation occurs in the context of chromosome loop structures called insulated neighborhoods, and recent studies have shown that these structures are altered and can contribute to oncogene dysregulation in various cancer cells. We review the types of genetic and epigenetic alterations that influence neighborhood structures and contribute to gene dysregulation in cancer, present models for insulated neighborhoods associated with the most prominent human oncogenes, and discuss how such models may lead to further advances in cancer diagnosis and therapy.

The ubiquitin-proteasome system plays a central role in regulating protein homeostasis in mammalian cells. It is a multistep process involving the polyubiquitination of proteins prior to their proteolytic degradation by the 26S proteasome complex. Blockade of this process results in the accumulation of proteins that are deleterious to the survival of cancer cells and has led to the approval of the proteasome inhibitors bortezomib and carfilzomib for the treatment of multiple myeloma and mantle cell lymphoma. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to recruit an E3 ubiquitin ligase to a specific target protein, thereby providing a mechanism to ubiquitinate and degrade specific pathological proteins. A significant body of preclinical data, generated since PROTACs were first introduced 15 years ago, demonstrates that PROTACs provide a robust approach to expose new cell biology and to generate novel therapeutics with the potential to target currently undruggable proteins.

The Hippo pathway has drawn increasing interest in the past decade for its role in the regulation of cell growth, differentiation, organ size, and tissue homeostasis. Recent studies have expanded our knowledge of known upstream regulators of the Hippo pathway and have consistently demonstrated that the Hippo pathway is critical for translating cellular cues into transcriptional responses by receiving input from a wide range of upstream signals. Dramatic overgrowth phenotypes upon deregulation of the Hippo pathway have prompted investigation into its role in cancer. Here we provide an overview of the Hippo pathway, our current understanding of its role in tumorigenesis, and potential therapeutics targeting Hippo signaling.

RAS proteins play a major, causal role in many human cancers. No therapies have been developed for these cancers because the RAS protein has been considered undruggable given that it has no accessible pocket to which a drug could bind with high affinity, and the mutant proteins that cause cancer are virtually identical to their essential, wild-type counterparts. New technologies in drug development, such as nuclear magnetic resonance–based fragment screening and covalent tethering, and new insights into RAS structure and function have changed this perception and facilitated the development of several drug candidates.

The von Hippel–Lindau (VHL) gene is a two-hit tumor suppressor gene and is linked to the development of the most common form of kidney cancer, clear cell renal carcinoma; blood vessel tumors of the retina, cerebellum, and spinal cord called hemangioblastomas; and tumors of the sympathoadrenal nervous system called paragangliomas. The VHL gene product, pVHL, is the substrate recognition subunit of a cullin-dependent ubiquitin ligase that targets the α subunits of hypoxia-inducible factor (HIF) for destruction when oxygen is plentiful. Mounting evidence implicates HIF2 in the pathogenesis of pVHL-defective tumors and has provided a conceptual foundation for the development of drugs to treat them that inhibit HIF2-responsive gene products such as VEGF and, more recently, HIF2 itself. pVHL has additional, noncanonical functions that are cancer relevant, including roles related to the primary cilium, chromosome stability, extracellular matrix formation, and survival signaling.

In just a few short years, CRISPR/Cas9 genome editing has fundamentally changed basic, agricultural, and biomedical research, but no field has felt a more profound impact than cancer research. The ability to quickly and precisely manipulate the genome has opened the floodgates for a new and more elaborate understanding of how genes and gene regulation influence disease. Here we review how the development and implementation of CRISPR-based technology is redefining the way we study cancer, and ultimately how it may be used to improve treatment outcomes.

The circadian molecular clock regulates and coordinates cellular metabolism with the organism's daily feeding and fasting cycle. Disruption of circadian rhythm, such as through jet lag or shift work, appears to heighten cancer risk in humans and accelerates tumorigenesis in animal models. The mammalian clock is a circuitry of transcription factors anchored by BMAL1-CLOCK, which drives diurnal oscillation of metabolic gene expression. The clock is independent of the cell cycle, but they can couple to coordinate normal cell proliferation. Expression of components of the clock, BMAL1 and PER2, appears decreased in human cancers. PER2 promotes p53 function, while BMAL1 expression is suppressed by MYC, linking key oncogenic drivers to the circadian clock. This review provides an overview of the clock, its regulation of metabolism, the connection to cancer shown in studies spanning from human epidemiology to cell biology, and the therapeutic implications of the circadian rhythm.

Oncolytic viruses are native or modified viruses that directly kill tumor cells but spare normal tissue and promote host antitumor immunity. Recently, an oncolytic herpes simplex virus (oHSV) type 1–encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF) demonstrated significant clinical benefit in a randomized phase III clinical trial for patients with advanced melanoma, leading to regulatory approval in 2015. In this review, we provide a general characterization of herpes simplex viruses and discuss methods for vector modification, which can help limit viral pathogenicity and immunogenicity while promoting antitumor immunogenicity. We also provide insight into general strategies for using oHSV agents in tumor immunotherapy regimens for the treatment of cancer and briefly review some of the currently emerging preclinical and clinical data that support an important role for such agents in the treatment of cancer.

Cellular senescence is a state of stable proliferative arrest triggered by various stimuli, including oncogenic and other cellular stress. Senescent cells are highly metabolically active and have diverse and profound nonautonomous effects through the senescence-associated secretory phenotype (SASP). It has become increasingly evident that senescent cells can have tumour suppressive or pro-oncogenic effects on adjacent cancer cells and other players in the tumor microenvironment such as the stroma, vasculature, and immune system. Thus, the last decade or so has witnessed a huge leap forward in our understanding of the biology of senescence, promoting it from an autonomous tumor suppressor to a complex, dynamic, and interactive phenotype. It is perhaps not a coincidence that the concept of the “hallmarks of cancer” has also evolved during this period, with the latest iteration (Hanahan & Weinberg 2011) focusing more on the microenvironment. Here, we suggest that cellular senescence could underpin the biology of many of the hallmarks of cancer, making it the true power behind the throne.

The successful development of prophylactic cancer vaccines targeting oncogenic viruses has demonstrated the potential for vaccination to reduce the global burden of cancer. However, most human cancers are not caused by viruses, and therefore novel approaches are needed for the successful development of prophylactic cancer vaccines for nonviral cancers. In this review, we detail evidence that the human immune system can recognize and eliminate non-virus-caused cancers before they become clinically apparent. We also discuss the design of an ideal prophylactic vaccine with the goal of providing a lasting adaptive immune response against antigen targets that arise early in a cancer's development.

The immune system has the potential to recognize and eliminate tumor cells, and failed immune surveillance contributes to cancer development. Many immunotherapeutics, including checkpoint blockade therapy, harness the endogenous antitumor immune response. While clinical benefit can be profound in some cases, some patients show primary resistance, whereas others experience clinical response and then develop secondary resistance under immune selective pressure. In this review, we discuss tumor cell–intrinsic mechanisms of primary and secondary immune evasion, both of which contribute to resistance to immunotherapeutic interventions. General mechanisms include adaptive evasion, allowing the tumor to establish equilibrium with an existing T cell infiltrate, and innate evasion, in which T cells and other immune cells are excluded from the tumor microenvironment. Evidence suggests that both processes can mediate resistance to checkpoint blockade therapy, but the different biological processes involved may necessitate distinct treatment strategies for overcoming resistance therapeutically.

Colorectal cancer (CRC) represents one of the leading causes of morbidity and cancer-related mortality in the world. While the etiology of CRC is believed to arise from genetic mutations, alterations in the gut microbiota composition also influence cancer incidence and progression. This review focuses on how gut microbiota and their relationship with the innate immune system link inflammation to genotoxicity and carcinogenesis.

Cell-intrinsic mechanisms of nutrient sensing are intimately linked to adaptive metabolic responses, and these pathways play critical roles in the complex and dynamic nutrient environment of a growing tumor. Nutrient-responsive transcription factors (e.g., HIF, SREBP, ATF4) and signaling pathways (e.g., mTORC1, AMPK) allow tumor cells to tune their metabolic output and strategies to fluctuations in nutrient availability, thus balancing tumor cell proliferation and survival with a combination of anabolic and adaptive responses. Coupling these nutrient-sensing mechanisms to the control of recycling and scavenging processes, such as autophagy and macropinocytosis, further enhances the adaptability to nutrients within tumors. Here, we discuss the key nutrient-sensing pathways active in cancer cells, how oncogenic events influence these pathways, and their likely contributions to tumor growth and survival. A better understanding of nutrient-sensing strategies and metabolic adaptations within the tumor microenvironment is critical to defining and targeting metabolic vulnerabilities in cancer.

Historically, it has been widely presumed that differentiated cells are determined during development and become irreversibly committed to their designated fates. In certain circumstances, however, differentiated cells can display plasticity by changing their identity, either by dedifferentiation to a progenitor-like state or by transdifferentiation to an alternative differentiated cell type. Such cellular plasticity can be triggered by physiological or oncogenic stress, or it can be experimentally induced through cellular reprogramming. Notably, physiological stresses that promote plasticity, such as severe tissue damage, inflammation, or senescence, also represent hallmarks of cancer. Furthermore, key drivers of cellular plasticity include major oncogenic and tumor suppressor pathways and can be exacerbated by drug treatment. Thus, plasticity may help cancer cells evade detection and treatment. We propose that cancer can be considered as a disease of excess plasticity, a notion that has important implications for intervention and treatment.

It has been 40 years since the US Food and Drug Administration approved the estrogen receptor (ER) antagonist tamoxifen for the treatment of ER-positive breast cancer, ushering in the era of targeted therapy coupled with a companion diagnostic. The prostate cancer field quickly followed suit with the approval of the androgen receptor (AR) antagonist bicalutamide. In the years since, there has been sustained scientific interest in understanding these hormone-dependent signaling pathways and in drug discovery efforts to identify novel hormone-directed therapeutic agents. Recently, there have been breakthrough discoveries relating to mechanisms that enable reactivation of ER and AR signaling in the presence of antihormonal agents and that enable loss of hormone dependency, providing multiple routes of acquired resistance to hormone therapy. This review discusses parallels between breast and prostate cancer, including their pathobiologies, existing therapeutic modalities, acquired resistance to such therapeutics, and novel therapies being developed to target distinct states of resistance.

Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

Recurrent driver mutations in the genes encoding histones have been recently described in pediatric brain tumors, as well as in chondroblastomas and giant cell tumors of the bone. The mutations are often heterozygous and frequently comprise single amino acid substitutions in the tails of histone variants. Substitutions of methionine to lysine on H3.3K27 or H3.3K36 are the most common alterations, occurring in diffuse intrinsic pontine gliomas (DIPGs) and chondroblastomas, respectively. Current data suggest that histone mutations alter the epigenetic landscape in tumor cells and lead to a blockade of differentiation, but the mechanisms underlying oncogenesis are not fully understood. These mutations also exhibit a propensity for exclusive expression in specific cell lineages and, in the case of brain tumors, a remarkable anatomic and developmental specificity. The histone mutations have raised interest in promising novel therapeutic strategies that incorporate epigenetic drugs.

Proteolysis plays critical roles in normal and pathologic physiology; these enzymes are intricately involved in cancer progression and spread. Our understanding of protease function has advanced from nonspecific degrading enzymes to a modern appreciation of their diverse roles in posttranslational modification and signaling in a complex microenvironment. This new understanding has led to next-generation diagnostics and therapeutics that exploit protease activity in cancer. For diagnostics, protease activity may be measured as a biomarker of cancer, with wide-ranging utility from early detection to monitoring therapeutic response. Therapeutically, while broad inhibition of protease activity proved disappointing, new approaches that more specifically modulate proteases in concert with secondary targets might enable potent combination therapies. In addition, clinical evaluation is underway for tools that leverage protease activity to activate therapeutics, ranging from imaging agents that monitor surgical margins to immunotherapies with improved specificity. Technologies that interact with, measure, or modulate proteases are poised to improve cancer management on diagnostic and therapeutic fronts to realize the promise of precision medicine.

Disseminated tumor cells (DTCs) are recognized as the seeds of metastasis. However, metastatic lesions can become symptomatic years or decades after primary tumor removal. This clinical finding suggests that DTCs are not immediately competent to initiate growth and can persist in a dormant state. Here we review recent data for three potential scenarios that could result in DTC dormancy: (a) The target organ microenvironment instructs DTCs to enter dormancy; (b) primary tumors pre-encode a dormancy signature that only becomes evident when DTCs enter target organs that produce dormancy-inducing cues; and (c) early dissemination spawns DTCs that, by virtue of being closely related to normal cells, would retain the capacity to respond to dormancy-instructing signals and enter dormancy in target organs. The literature supports the existence of these scenarios and provides insight into how to prevent metastasis. Importantly, cotargeting dormant and proliferative DTCs in stage IV cancer may also improve outcomes in this clinical setting.