Asynchronous Evolution of Epithelium and Stroma Differentiates Precursor Lesions from Pancreatic Cancer
Year: 2026
Type: article
Abstract: Pancreatic intraepithelial neoplasia (PanIN) precedes pancreatic cancer, a deadly disease characterized by an extensive tumor microenvironment. How the microenvironment evolves during cancer progression is largely unknown, as PanINs are microscopic and nondiseased pancreas samples are exceedingly rare, while adjacent normal samples are disrupted by the presence of malignancy. Leveraging donor organs and spatial technologies, we mapped the evolution of PanIN to cancer. The PanIN epithelial component falls on a continuum with cancer, whereas the PanIN microenvironment is drastically distinct. Progression to cancer is accompanied by profound geographic reorganization of myeloid cells and lymphocytes and the formation of a cancer-specific fibroblast population characterized by high levels of smooth muscle actin, LRRC15, and the WNT signaling component LEF1. Together, our data show asynchronous evolution of epithelial and stromal components during pancreatic carcinogenesis. Lack of stromal reprogramming might explain why most PanINs do not progress to cancer. Compiled data available at https://www.pancreas-precancer-atlas.com/. SIGNIFICANCE: Pancreatic cancer precursor lesions are widely prevalent in the population, but progression to invasive cancer is uncommon. Identifying barriers to cancer progression is critical for cancer interception. Our findings describe unique features of the precancer microenvironment that are likely responsible for keeping precursor lesions from progressing to malignancy.
Source: Cancer Discovery
Authors: Ahmed M. Elhossiny, Padma Kadiyala, Jude O. Okoye, Harrison L. Hiraki, Megan C. Procario, Thejaswini Giridharan, Hannah R. Watkoske, Mariana Tannus Ruckert, Jiayue Wang, Brian D. Griffith, Alexander W. Bray, Jamie N. Mills, Carlos E. Espinoza, Jörg Zeller, Nicole Peterson, Filip Bednar, Yaqing Zhang, Arvind Rao, Costas A. Lyssiotis, Julianne M. Szczepanski, Jiaqi Shi, Atul Deshpande, Anirban Maitra, Elana J. Fertig, Eileen S. Carpenter, Timothy L. Frankel, Marina Pasca di Magliano
Institutions: University of Michigan, Nnamdi Azikiwe University, Michigan Medicine, U-M Rogel Cancer Center, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, NYU Langone Health, NYU Langone’s Laura and Isaac Perlmutter Cancer Center, New York University, University of Maryland, Baltimore, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, VA Ann Arbor Healthcare System, Ann Arbor VA Medical Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1404790370, G1686049839, G1862641557, G1950921013, G2071835008, G2667619115, G30797128, G3233328209, G3940157654, G4280471095, G4564883074, G5302875174, G7987674788, Defining epigenetic signaling to reshape pancreatic tumor microenvironment, University of Michigan Rogel Cancer Center Support Grant 2023-2028, Dissecting the role of Notch signaling in the pancreatic cancer microenvironment., PASSCODE (Pancreatic Adenocarcinoma Stromal Reprograming ConSortium COordination, Data Management and Education)
OpenAlex ID: W7162013298