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.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Miyabayashi K,Baker LA,Deschênes A,Traub B,Caligiuri G,Plenker D,Alagesan B,Belleau P,Li S,Kendall J,Jang GH,Kawaguchi RK,Somerville TDD,Tiriac H,Hwang CI,Burkhart RA,Roberts NJ,Wood LD,Hruban RH,Gillis J,Krasnitzdoi
10.1158/2159-8290.CD-20-0133subject
Has Abstractpub_date
2020-10-01 00:00:00pages
1566-1589issue
10eissn
2159-8274issn
2159-8290pii
2159-8290.CD-20-0133journal_volume
10pub_type
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