Cell of Origin Influences Pancreatic Cancer Subtype
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- 1 March 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 11 (3), 660-677
- https://doi.org/10.1158/2159-8290.CD-20-0633
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell-derived and acinar cell-derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. SIGNIFICANCE: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention.Keywords
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Funding Information
- NCI R35 (CA197591)
- Blavatnik Family Fellowship
- NIH Director's Pioneer Award (DP1-CA238296)
This publication has 55 references indexed in Scilit:
- Pancreatic cancer: why is it so hard to treat?Therapeutic Advances in Gastroenterology, 2013
- Pancreatitis-Induced Inflammation Contributes to Pancreatic Cancer by Inhibiting Oncogene-Induced SenescenceCancer Cell, 2011
- Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancerProceedings of the National Academy of Sciences, 2010
- Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-RasCancer Cell, 2009
- Ras Activity Levels Control the Development of Pancreatic DiseasesGastroenterology, 2009
- Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult miceProceedings of the National Academy of Sciences, 2008
- Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult MiceCancer Cell, 2007
- SOX9 is required for maintenance of the pancreatic progenitor cell poolProceedings of the National Academy of Sciences, 2007
- Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancerGenes & Development, 2006
- Both p16 Ink4a and the p19 Arf -p53 pathway constrain progression of pancreatic adenocarcinoma in the mouseProceedings of the National Academy of Sciences, 2006