Pancreatic Cancer
Series edited by Ben Z. Stanger
Pancreatic ductal adenocarcinoma (PDAC) has among the poorest prognosis and highest refractory rates of all tumor types. The reviews in this series, by Dr. Ben Z. Stanger, bring together experts across multiple disciplines to explore what makes PDAC and other pancreatic cancers so distinctively challenging and provide an update on recent multipronged approaches aimed at improving early diagnosis and treatment.
Articles in series
Abstract
Authors
Minh T. Than, Ben Z. Stanger
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
The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered “undruggable,” KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.
Authors
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
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) 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
Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, including patient performance status, metastatic disease at diagnosis, intrinsic drug resistance, and a highly complex tumor microenvironment. Emerging targeted therapies, such as RAS inhibitors, offer promise for personalized treatment. These developments have prompted precision medicine–focused clinical trials using molecular subtyping for patient stratification. Effective development of precision medicine therapies depends heavily on robust preclinical models capable of accurately recapitulating the complexities of the pancreatic tumor microenvironment. Two-dimensional, air-liquid interface, and patient-derived organoid cultures combined with in vivo genetically engineered mouse models and patient-derived xenografts represent valuable experimental systems. This Review critically examines the strengths and limitations of these experimental model systems. We highlight their relevance and utility for advancing precision medicine strategies in pancreas cancer.
Authors
Vasiliki Pantazopoulou, Casie S. Kubota, Satoshi Ogawa, Kevin Christian Montecillo Gulay, Xiaoxue Lin, Hyemin Song, Jonathan R. Weitz, Hervé Tiriac, Andrew M. Lowy, Dannielle D. Engle
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)