Annual Review of Cancer Biology - Current Issue

Pancreatic cancer is a notoriously deadly disease characterized by many challenges in clinical management. Despite important advances in our understanding of pancreatic cancer progression and its underlying molecular biology over the last decades, there is a long road ahead if we aim to meaningfully improve patient outcomes in this difficult disease. Treatment options remain limited, and patient prognosis, although improving, remains bleak. As we build toward the future, we propose a framework for targeting the seven deadly hallmarks of pancreatic cancer in an effort to cure this disease. The high mortality and aggressive nature of pancreatic cancer can be largely ascribed to (a) diagnostic deficiencies, (b) chronic inflammation, (c) desmoplastic stroma, (d) early metastasis, (e) KRAS signaling, (f) metabolism, and (g) rapid deconditioning. Here, we outline the challenges presented by each of these disease hallmarks and highlight ongoing research to tackle each one.

Cancers, a leading cause of morbidity and mortality worldwide, are undergoing notable shifts in incidence patterns. Cancer subtypes generally associated with advancing age are now increasingly being diagnosed in younger populations, while gender disparities in cancer susceptibility have fluctuated across various malignancies. Some cancer subtypes previously confined to specific geographical populations are now globally prevalent. Remarkably, these changing patterns of cancer incidence have occurred despite relatively stable mutational landscapes specific to each cancer type, highlighting the role of environmental exposures (exposomes) as potential drivers of these trends. Intriguingly, evidence suggests that the exposome may exert some of its influence through nonmutagenic mechanisms, although the precise ways in which environmental carcinogens trigger or promote cancer development remain poorly understood. This review summarizes the current understanding of the mutagenic and nonmutagenic mechanisms through which carcinogens, including tobacco smoke, air pollutants, metals, diet, and alcohol, impact cancer development, as this may help inform precision prevention and public health policy.

Alterations in the genome that drive the transformation of normal cells into malignant cells program cancer initiation and progression. This rewiring also induces unique dependencies for genes and pathways that can be targeted therapeutically. Even though we have a clearer view of the spectrum of these molecular alterations, we still lack a complete understanding of how these alterations affect biological processes and create specific vulnerabilities in cancer cells. To address this, we have created the Cancer Dependency Map (DepMap) to systematically identify and map cancer vulnerabilities. Here, we provide an overview of the history and development of the current DepMap. We also highlight biological insights enabled by DepMap. Findings from DepMap will provide insights into new targets suitable for drug discovery efforts.

Mitochondrial respiratory chain (RC) activity is essential for in vivo cell proliferation, particularly in cancer, CD4⁺ and CD8⁺ T cells, and endothelial cells involving ATP production and biosynthesis. The RC is essential for the oxidative tricarboxylic acid (TCA) cycle to produce intermediates that funnel into anabolic pathways to synthesize lipids, proteins, and nucleotides. By contrast, mitochondrial respiration has a distinct role in other proliferating cells including regulatory T cells (Tregs) and stem cells whereby mitochondria are dispensable for in vivo cell proliferation but determine cell fate and function through several signaling mechanisms. In this review, we discuss how the mitochondrial RC is an anabolic engine that supports the proliferation of cancer cells, CD4⁺ and CD8⁺ T cells, and endothelial cells while mitochondria serve as central hubs that integrate metabolic signals to control Treg and stem cell fate and function in vivo.

Enhancers are noncoding DNA sequences responsible for orchestrating gene expression programs by interacting with transcription factors and chromatin regulators within complex genome structures. However, their fundamental functions can be disrupted by genetic and epigenetic alterations, leading to aberrant enhancer activation or rewiring that contributes to oncogenesis. Analyzing dysregulated enhancer landscapes reveals new subtype-defining genomic features, such as enhancer hijacking, and identifies disease-relevant transcriptional regulators as potential targets for developing enhancer-targeting therapeutic strategies. Here, we delve into evolving concepts and technologies for studying enhancers; discuss how genetic, epigenetic, and topological alterations disrupt enhancer regulation to promote oncogenic gene expression; and underscore the importance of understanding the regulatory principles governing enhancer function to guide therapeutic strategies. Furthermore, we highlight key challenges and emerging opportunities in targeting enhancers and their regulators to improve cancer classification, prognosis, and treatment.

Each cancer is the result of an individually unique evolutionary process. Yet, as demonstrated by extensive genetic analyses of human specimens, the genetic endpoints of cancers across different tissues are remarkably specific, with individual cancer driver genes being typically associated with only a limited set of tumor types. Tissue and cellular contexts thus impose strong and genetically predictable evolutionary constraints on carcinogenesis. Lineage-specific transcription factors, central regulators of organismal development, tissue homeostasis, and regeneration, often also support cancer cell fitness in a lineage-specific manner. In this review, we discuss recent results on the interactions between transcriptional lineage factor programs and oncogenic pathways and how such interactions may determine the oncogenic competence of cancer-associated genetic alterations. These developments are starting to shed light on the molecular basis of tissue specificity in carcinogenesis, with relevance for cancer prevention and therapy.

The development of novel drug modalities is necessary to overcome the current critical issues in the treatment of cancer, namely toxicity, insufficient efficacy, and the development of resistance. Unlike classical small molecule inhibitors that only block a single function or interaction of a protein involved in oncogenic signaling, proteolysis-targeting chimeras (PROTACs) degrade the entire protein, thus offering a potential paradigm shift. PROTACs are bivalent small molecules that recruit a target protein in proximity to an E3 ligase, promoting the transfer of ubiquitin, which marks the protein for proteasomal degradation. Because of their unique properties, PROTACs offer an attractive alternative as targeted therapeutics. The first PROTAC entered the clinic 5 years ago, and since then more than 30 have followed. In this review, we discuss the current compounds being investigated in the clinic, the key aspects of their design, and their potential for treating cancer.

CRISPR activation (CRISPRa) co-opts nuclease-dead Cas-molecule DNA-binding capabilities to direct transcriptional activators to specific loci, driving gene expression. CRISPRa technology has advanced rapidly in the past few years, and it is now applicable to a wide range of biological questions, including the study of cancer. In this review, we discuss the different forms of CRISPRa technologies, their in vitro and in vivo applications, and recent studies that have used CRISPRa in their cancers of choice. We further discuss the different CRISPRa tools that are available, including mouse models and single-guide RNA libraries. Finally, we examine the maturation of CRISPRa, as its potential therapeutic applications are beginning to be explored.

The mitochondrial genome, which encodes genes essential for respiration and cellular homeostasis, is the target of abundant and highly diverse somatic alterations in cancers. Somatic alterations to mitochondrial DNA (mtDNA) nearly always arise heteroplasmically, producing heterogeneous ensembles of mtDNA within single cells. Here, we review new insights derived from exponential increases in genomic sequencing data that have uncovered the nature of, selective pressure for, and functional consequences of cancer-associated mtDNA alterations. As many discoveries have been limited by their ability to determine cell-to-cell variation in mtDNA genotype, we describe a new generation of single-cell sequencing approaches that resolve otherwise indeterminate models of mtDNA heteroplasmy. In tandem with novel approaches for mtDNA editing and modeling of mutations, these advances foreshadow the quantitative dissection of dosage-dependent mtDNA phenotypes that underlie both tumor evolution and heterogeneous response to therapies.

A surge of recent studies have identified B cells as pivotal contributors to shaping the tumor microenvironment (TME) within solid tumors. B cells can both directly and indirectly antagonize tumor growth via antibody production, antigen presentation, and cytokine secretion, potentially through the formation of tertiary lymphoid structures. However, certain B cell states have demonstrated the ability to promote tumor growth via immunoregulatory mechanisms such as the production of immunosuppressive cytokines and the expression of immune checkpoints, both of which dampen T cell–dependent antitumor responses. Here, we discuss the dichotomy of B cell function in solid tumors, underscoring both the pro- and antitumor roles that B cells play in the TME. Furthermore, we summarize ongoing efforts to reprogram protumorigenic B cells and/or to promote the activity and abundance of effector B cells as potential immunotherapy approaches in solid tumors.

Minimal residual disease (MRD) represents a significant challenge in the treatment of various cancers, acting as a precursor to relapse and therapeutic resistance. This review discusses the clinical background of MRD, exploring its role as a critical determinant in patient outcomes. The persistence of MRD is attributed to several mechanisms, including Darwinian selection of preexisting resistant clones, Lamarckian induction of resistance traits, and pharmacologic resistance due to the tumor's intrinsic barriers to drugs and treatment limitations. These processes underscore MRD as the seed for long-term drug resistance, complicating treatment efficacy. Addressing MRD requires innovative therapeutic strategies, ranging from targeted therapies to novel drug combinations, aimed at eradicating these resilient cancer cells. By understanding and targeting MRD, we could improve patient prognoses and develop more effective cancer treatments. This review synthesizes current knowledge and emerging approaches in the quest to manage and eliminate MRD.

The selective vulnerability of BRCA1/2-mutated (BRCA^mut) cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors provides one of the best examples of synthetic lethality that has been translated into the clinic. The success of this approach has led to a paradigm shift, with four PARP inhibitors now approved by the US Food and Drug Administration (FDA) for the treatment of ovarian, breast, prostate, and/or pancreatic cancers with BRCA^mut. Furthermore, recent preclinical and clinical data suggest that many other types of solid tumors might also benefit from PARP inhibitors, regardless of their BRCA^mut status. Despite this progress, resistance to PARP inhibitors is frequently observed in the clinic, which is, at least in part, due to the incomplete understanding of the mechanism of action of PARP inhibitors. In this review, we summarize the diverse processes underlying the signaling mechanisms of the PARP enzymes. We also discuss recent progress in utilizing these mechanistic insights for overcoming PARP inhibitor resistance, developing predictive biomarker assays, designing rational combination therapies, and, finally, developing the next-generation PARP1-targeting agents with a more complete and durable therapeutic response.

Nongenetic plasticity has emerged as a key driver of cancer drug resistance, yet its precise origins, nature, and consequences are not fully clarified. This review examines technological, computational, and conceptual developments in the nongenetic determinants of drug resistance. We begin by proposing refined definitions of cellular state, fate, and plasticity. We subsequently contextualize the findings from multimodal approaches to investigate plasticity, highlighting how new single-cell lineage-tracing methods provide opportunities for quantitatively capturing state transitions, their timescales and heritability, and how they contribute to resistance mechanisms. We also draw parallels with concepts from developmental biology and microbial persistence research. Next, we cover the role that computational approaches have played in revealing the otherwise latent patterns of heterogeneity that underlie plasticity from complex datasets. We conclude by emphasizing the need for standardized terminology in this rapidly evolving field and the path from bench to bedside.

Despite its relatively recent emergence, single-cell sequencing has cemented its place in scientific research. It has grown exponentially in less than two decades since its start, with broad impact in the biological sciences. The blood represents an attractive system for early development and application of single-cell technologies. As a result, single-cell analyses in blood and leukemia have led the way in describing how cellular heterogeneity affects cancer progression. In this review, we discuss the technological and conceptual advances brought by single-cell genomics, ranging from genetic evolution and differentiation states that mediate drug resistance to the complex interactions required for immunotherapy responses. These high-resolution insights are starting to enter clinical assessment.

Preclinical models have played a pivotal role in the development of immunotherapies that now have become a standard treatment option for numerous cancer types. This review examines the strengths and weaknesses of various mouse models in advancing our understanding of cancer immunology and responses to immunotherapy. Furthermore, we explore how emerging technologies such as humanized models, the integration of CRISPR/Cas9 systems, and advanced in vitro systems are helping us deepen our insights into cancer–immune interactions that dictate the response to therapies. Integrating these diverse models with cutting-edge genetic and genomic tools will be crucial to tackle challenges such as immunotherapy resistance and to design the next generation of cancer immunotherapy drugs.

Lactate, once considered an inert byproduct of glycolysis, is now increasingly appreciated as a metabolite with diverse roles in cellular metabolism and physiologic regulation. Our understanding of the role of lactate in biological systems can be considered in two categories: metabolic substrate and metabolic signal. These shared roles of lactate can be reconciled through the lens of a metabolite that is suited to regulate cellular function to license adaptation in line with the bioenergetic state of the cell. The mechanisms through which lactate production, transport, and consumption occur within cells and organisms are an area of longstanding and still active research. Here, we focus on how lactate production and utilization as a metabolic substrate feed into its role as a metabolic signal and the emerging mechanisms through which it regulates biological processes.