Asynchronous evolution of epithelium and stroma differentiates precursor lesions from pancreatic cancer
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 non-diseased 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 while the PanIN microenvironment is drastically distinct. Progression to cancer is accompanied by profound geographical 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://pascadimagliano-lab.github.io/PancAtlas.
Authors
- Mariana T. Ruckert (ORCID: https://orcid.org/0000-0002-8282-4454)
- Ahmed M. Elhossiny (ORCID: https://orcid.org/0000-0003-0884-8754)
- Hannah R. Watkoske (ORCID: https://orcid.org/0000-0003-2518-6457)
- Thejaswini Giridharan (ORCID: https://orcid.org/0000-0003-0512-577X)
- Eileen S. Carpenter (ORCID: https://orcid.org/0000-0001-6775-6943)
- Jude Ogechukwu Okoye (ORCID: https://orcid.org/0000-0002-7194-5592)
- Julianne M. Szczepanski (ORCID: https://orcid.org/0000-0002-5687-9857)
- Jörg Zeller
- Megan C. Procario (ORCID: https://orcid.org/0000-0002-2501-2548)
- Carlos E. Espinoza
- Padma Kadiyala (ORCID: https://orcid.org/0000-0002-3273-9905)
- Harrison L. Hiraki (ORCID: https://orcid.org/0000-0002-6199-0744)
- Jamie N. Mills
- Atul Deshpande
- Marina Pasca di Magliano (ORCID: https://orcid.org/0000-0001-9632-9035)
- Alexander W. Bray (ORCID: https://orcid.org/0000-0002-1849-2555)
- Timothy L. Frankel (ORCID: https://orcid.org/0000-0001-5987-0404)
- Costas A. Lyssiotis (ORCID: https://orcid.org/0000-0001-9309-6141)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Brian D. Griffith (ORCID: https://orcid.org/0000-0001-6580-7217)
- Jiaqi Shi (ORCID: https://orcid.org/0000-0003-4893-1587)
- Anirban Maitra (ORCID: https://orcid.org/0000-0001-7923-9978)
- Arvind Rao (ORCID: https://orcid.org/0000-0002-9613-426X)
- Filip Bednar (ORCID: https://orcid.org/0000-0001-5193-9817)
- Jiayue Wang (ORCID: https://orcid.org/0009-0006-1005-0652)
- Nicole Peterson (ORCID: https://orcid.org/0009-0000-6035-4124)
- Yaqing Zhang (ORCID: https://orcid.org/0000-0002-9185-4364)
Institutions
- University of Maryland, Baltimore (US)
- University of Alabama at Birmingham Hospital (US)
- Johns Hopkins University (US)
- University of Michigan (US)
- Johns Hopkins Medicine (US)
- NYU Langone Health (US)
- Michigan Medicine (US)
- Ann Arbor Center for Independent Living (US)
- Johns Hopkins Hospital (US)
- University of Baltimore (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-05-21
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-2001
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00