Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes

Koji Miyabayashi, Lindsey A. Baker, Astrid Deschênes, Benno Traub, Giuseppina Caligiuri, Dennis Plenker, Brinda Alagesan, Pascal Belleau, Siran Li, Jude Kendall, Gun Ho Jang, Risa Karakida Kawaguchi, Tim D.D. Somerville, Hervé Tiriac, Chang Il Hwang, Richard A. Burkhart, Nicholas J. Roberts, Laura D. Wood, Ralph H. Hruban, Jesse GillisAlexander Krasnitz, Christopher R. Vakoc, Michael Wigler, Faiyaz Notta, Steven Gallinger, Youngkyu Park, David A. Tuveson

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner rep-resenting the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.

Original languageEnglish (US)
Pages (from-to)1566-1589
Number of pages24
JournalCancer discovery
Volume10
Issue number10
DOIs
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Oncology

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