학술논문
A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma
Document Type
article
Author
Lytle, Nikki K; Ferguson, L Paige; Rajbhandari, Nirakar; Gilroy, Kathryn; Fox, Raymond G; Deshpande, Anagha; Schürch, Christian M; Hamilton, Michael; Robertson, Neil; Lin, Wei; Noel, Pawan; Wartenberg, Martin; Zlobec, Inti; Eichmann, Micha; Galván, José A; Karamitopoulou, Eva; Gilderman, Tami; Esparza, Lourdes Adriana; Shima, Yutaka; Spahn, Philipp; French, Randall; Lewis, Nathan E; Fisch, Kathleen M; Sasik, Roman; Rosenthal, Sara Brin; Kritzik, Marcie; Von Hoff, Daniel; Han, Haiyong; Ideker, Trey; Deshpande, Aniruddha J; Lowy, Andrew M; Adams, Peter D; Reya, Tannishtha
Source
Cell. 177(3)
Subject
Language
Abstract
Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.