Review
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal cancers, with metastasis as the primary driver of mortality. While metastatic mechanisms are shared across malignancies, PDAC metastasis poses unique therapeutic challenges due to the presence of extensive tumor heterogeneity, desmoplasia, and immunosuppression — features that enable diverse migratory behaviors and therapeutic resistance. Recent advances have shown that metastatic progression in PDAC emerges from dynamic interactions between tumor cell–intrinsic and microenvironmental factors, each adapting to evolving stressors throughout the metastatic cascade. In the primary tumor, genomic instability and epigenetic reprogramming generate subclones with heightened invasive potential, while dense stromal reactions and myeloid-dominated immune suppression facilitate escape. During circulation, PDAC cells employ distinctive survival strategies through homotypic clustering and heterotypic interactions with blood components. At distant sites, PDAC cells adapt to organ-specific microenvironments through context-dependent metabolic and immune modulation, resulting in phenotypes that diverge from the primary tumor. In this Review, we examine how tumor-stroma crosstalk mechanisms shape metastatic progression in PDAC, provide a framework for understanding why conventional therapies often fail against metastatic disease, and highlight emerging opportunities for stage- and site-specific therapeutic interventions that target these unique adaptations.
Authors
Ravikanth Maddipati
Abstract
Despite advances in multidisciplinary oncology care, curing patients diagnosed with pancreatic duct adenocarcinoma (PDAC) remains all too uncommon. In this Review, we discuss evolving concepts to guide the care of patients with operable PDAC, focusing on adjuvant and neoadjuvant systemic therapies, the ever-controversial topic of radiation therapy, and the emerging role of cancer vaccines. Given the promise of biomarkers to better predict therapeutic response, the development of KRAS inhibitors, our ability to deliver higher doses of radiation therapy more precisely and safely, and the technology to rapidly produce highly personalized cancer vaccines, there is reason to expect that the guidelines for the care of our patients with operable PDAC will change rapidly in the next few years.
Authors
John M. Bryant, Luis Ruffolo, Kevin Soares, Sarah Hoffe, Andrew M. Lowy
Abstract
The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.
Authors
Colin Sheehan, Alexander Muir
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known to progress from one of two main precursor lesions: pancreatic intraepithelial neoplasia (PanIN) or intraductal papillary mucinous neoplasm (IPMN). The poor survival rates for patients with PDAC, even those diagnosed with localized disease, highlight the need for pancreatic cancer interception at the precursor stage. Although their basic biological drivers are well characterized, practical strategies for PanIN and IPMN interception remain elusive due to difficulties with detection, risk stratification, and low-morbidity intervention. Recently, advances in liquid biopsy, spatial multiomics analysis, and machine learning technology have provided deeper understanding of the molecular landscapes underlying pancreatic precursor development and progression. In this Review, we outline the different histologic phenotypes, clinical characteristics, and neoplastic cell–intrinsic and –extrinsic drivers of PanINs and IPMNs, with particular focus on current and potential future opportunities for pancreatic precancer interception.
Authors
Brian A. Pedro, Laura D. Wood
Abstract
Authors
Minh T. Than, Ben Z. Stanger
Abstract
Endometriosis is an estrogen-dependent chronic inflammatory syndrome characterized by viable endometrial tissue outside the uterine cavity and associated with pain and infertility. Endometriosis, as tissue or a pathological process, is dynamic in that its establishment and progression require repeated episodes of retrograde travel of shed endometrial tissue, which implants in the lower abdominal cavity following ovulatory cycles and survives. Estrogen-rich follicular fluid released onto peritoneal surfaces during ovulation may also support endometriotic implants. DNA evidence indicates that endometriosis originates from eutopic endometrial tissue, which may reach the abdominal cavity in a retrograde manner primarily via the uterine tubes. Unlike uterine bleeding associated with non-ovulatory circumstances, retrograde menstruation following an ovulation maximizes shedding of epithelial cells localized to deep invaginations of the basalis portion of the endometrium, which likely carry somatic cancer-driver mutations such as KRAS. The attached endometrial stromal cells are mostly mutation free but display epigenetic defects including overexpression of aromatase and estrogen receptor-β and downregulation of progesterone receptor, causing estrogen excess and progesterone resistance. These tissue clones may form implants in involuting ovarian corpus luteum cysts and peritoneal surfaces and induce tissue remodeling and fibrosis, manifested as deep-infiltrating endometriosis. The first-line treatment for chronic pelvic pain associated with endometriosis is suppression of ovulation, with the goal of relieving pain. Infertility is often managed using in vitro fertilization, which improves the embryo quality and alters endometrial development.
Authors
Serdar E. Bulun
Abstract
Cancer care is being transformed by therapies leveraging T lymphocytes to attack tumor cells. In parallel, recent basic discoveries have converged into a framework of lymphocyte-dependent immunity as a regenerative process that is sometimes outstripped by high-level engagement. In a stem cell–like fashion, selected T cells must balance mutually opposing demands of differentiation and self-renewal. Activating versus inhibitory signals to T cells instruct opposing cell metabolism, linked to alternative cell fates that arise in sibling cells through lopsided information transfer. Emerging studies indicate that durable immunotherapy response may be limited by the abundance of self-renewing T cells. Leveraging of basic discoveries of regenerative signaling to bolster sustained, stem-like output of freshly differentiated T cells is offering new strategies to overcome cancer immunotherapy resistance. Lymphocyte regeneration may also sustain harmful autoimmune attack. Undercutting the self-renewal of pathogenic clones may thus emerge as a therapeutic strategy for autoimmune diseases.
Authors
Steven L. Reiner
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common pediatric liver disease, affecting approximately 10% of children. Its prevalence is rising at an alarming rate, with cases increasingly identified even in early childhood. While MASLD shares key features across the lifespan, its earlier onset reflects developmental vulnerabilities and unique mechanistic drivers. Perinatal influences, including maternal obesity, gestational diabetes, and early-life nutritional exposures, play a central role by disrupting metabolic programming, driving mitochondrial dysfunction, and inducing epigenetic modifications. These early stressors interact with genetic predispositions, such as PNPLA3 and TM6SF2 variants, to amplify susceptibility and shape disease severity. Pediatric MASLD also exhibits distinct histological features, particularly predominant periportal (zone 1) steatosis, inflammation, and fibrosis, which contrast with the centrilobular or pericentral (zone 3) patterns often seen in adults. These findings provide insight into spatial heterogeneity, developmental pathophysiology, and unique disease progression trajectories in children. Addressing MASLD in children requires pediatric-specific approaches to diagnosis, risk stratification, and intervention. By integrating epidemiological trends, mechanistic insights, and translational advances, this Review highlights opportunities for targeted therapies and prevention strategies aimed at mitigating early-life drivers of MASLD, reducing disease burden, and improving long-term outcomes.
Authors
Jeffrey B. Schwimmer, Sudha B. Biddinger, Samar H. Ibrahim
Abstract
Metabolic dysfunction–associated steatohepatitis (MASH), the progressive inflammatory form of MASLD, is now a leading cause of chronic liver disease worldwide. Driven by obesity and type 2 diabetes, MASH significantly increases the risk of cirrhosis, hepatocellular carcinoma, and liver failure. While public health interventions remain essential, therapeutic strategies targeting metabolic dysfunction, inflammation, and fibrosis are urgently needed. This Review focuses on pharmacological treatments in advanced development, including incretin-based therapies (GLP-1, dual, and triple agonists), metabolic modulators (PPAR, FGF21, and THR-β agonists), and novel agents such as fatty acid synthase inhibitors. Current regulatory approval is based on histological end points, with increasing interest in noninvasive biomarkers and personalized treatment approaches. Recent trials with agents such as semaglutide, tirzepatide, survodutide, lanifibranor, pegozafermin, and resmetirom demonstrate substantial promise in resolving MASH and improving fibrosis, but unresolved issues remain regarding treatment duration, response heterogeneity, and long-term adherence. Genetic variants (e.g., PNPLA3 polymorphisms) and emerging molecular biomarkers may enhance stratification, while artificial intelligence is beginning to shape trial design and drug development. As the field moves toward combination therapies and precision medicine, the definition of therapeutic success will likely evolve to reflect both histological improvement and patient-reported outcomes. This Review provides a timely synthesis of the landscape, challenges, and future directions in MASH therapeutics.
Authors
Philip N. Newsome, Rohit Loomba
Abstract
Animal experiments have long been a cornerstone of advancements in biomedical research, particularly in developing novel therapeutic strategies for inflammatory and autoimmune diseases. However, these historically important approaches are now facing growing scrutiny for ethical reasons, concerns about translational limitations to human biology, and the rising availability of animal-free research methods. This shift raises a critical question: How relevant and effective are animal models for driving future advancements in today’s research landscape? This Review aims to explore this question within the field of biomedical research on the complement system, critically evaluating the contribution of animal models to the recent advancements and clinical successes of complement-targeted therapies. Specifically, we assess areas where animal studies have been indispensable for elucidating disease mechanisms and conducting preclinical evaluations, alongside instances where findings from animal models failed to translate successfully to human trials. Furthermore, we discuss similarities and differences in the complement system between animals and humans and explore innovations in animal research designed to improve translatability to human biology. By assessing the contributions of animal studies to complement therapeutics, this Review aims to provide insights into animal models’ strengths, limitations, and evolving role in complement research.
Authors
Felix Poppelaars, V. Michael Holers, Joshua M. Thurman
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