Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes
- 1 October 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (10), 1566-1589
- https://doi.org/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. 1426Keywords
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Funding Information
- NIH (P30CA045508)
- Cold Spring Harbor Laboratory Association V Foundation Thompson Foundation NIH (P30CA45508, P20CA192996, U10CA180944, U01CA224013, U01CA210240, R01CA188134, R01CA190092)
- Simons Foundation (552716)
- NIH (R01CA229699)
- NCI (R50CA211506)
- NCI (F30CA200240)
- Pershing Square Sohn Cancer Research Alliance Cold Spring Harbor Laboratory Northwell Health Affiliation NCI (5P01CA013106-Project 4, 1RO1CA229699)
- Daniel and Janet Mordecai Foundation (16-20-25-VAKO)
- Daiichi Sankyo Foundation of Life Science
- Uehara Memorial Foundation, Japan
- German Research Foundation (TR 1663/1)
- German Research Foundation (PL 894/1-1)
- State of New York (C150158)
- NIH (F32CA192904)
- NIH (F32CA180717)
- Sol Goldman Pancreatic Cancer Research Center
- Simons Foundation Life Sciences Founders Directed Giving-Research (519054)
- Breast Cancer Research Foundation (18-174)
This publication has 76 references indexed in Scilit:
- Improved tools for the Brainbow toolboxNature Methods, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Pancreatic cancer genomes reveal aberrations in axon guidance pathway genesNature, 2012
- Expression and Function of the Kallikrein-Related Peptidase 6 in the Human Melanoma MicroenvironmentJournal of Investigative Dermatology, 2011
- Proteolytic action of kallikrein-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal hemopexin domainsBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and ProgressionCancer Cell, 2011
- ConsensusClusterPlus: a class discovery tool with confidence assessments and item trackingBioinformatics, 2010
- Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicineBritish Journal of Cancer, 2010
- KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinomaBritish Journal of Cancer, 2009
- A Gene Expression Signature Associated with “K-Ras Addiction” Reveals Regulators of EMT and Tumor Cell SurvivalCancer Cell, 2009