Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes.

Miyabayashi, Koji, Baker, Lindsey A, Deschênes, Astrid, Traub, Benno, Caligiuri, Giuseppina, Plenker, Dennis, Alagesan, Brinda, Belleau, Pascal, Li, Siran, Kendall, Jude, Jang, Gun Ho, Kawaguchi, Risa Karakida, Somerville, Tim DD, Tiriac, Hervé, Hwang, Chang-Il, Burkhart, Richard A, Roberts, Nicholas J, Wood, Laura D, Hruban, Ralph H, Gillis, Jesse, Krasnitz, Alexander, Vakoc, Christopher R, Wigler, Michael, Notta, Faiyaz, Gallinger, Steven, Park, Youngkyu, Tuveson, David A (October 2020) Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes. Cancer Discovery, 10 (10). pp. 1566-1589. ISSN 2159-8274

URL: https://www.ncbi.nlm.nih.gov/pubmed/32703770
DOI: 10.1158/2159-8290.CD-20-0133

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 representing 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.See related commentary by Pickering and Morton, p. 1448.This article is highlighted in the In This Issue feature, p. 1426.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Gillis Lab
CSHL labs > Krasnitz lab
CSHL labs > Tuveson lab
CSHL labs > Vakoc lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL Cancer Center Program > Cellular Communication in Cancer Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: October 2020
Date Deposited: 11 Jan 2021 17:32
Last Modified: 13 Jul 2021 19:21
PMCID: PMC7664990
URI: https://repository.cshl.edu/id/eprint/39800

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