1. A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.
- Author
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Lytle NK, Ferguson LP, Rajbhandari N, Gilroy K, Fox RG, Deshpande A, Schürch CM, Hamilton M, Robertson N, Lin W, Noel P, Wartenberg M, Zlobec I, Eichmann M, Galván JA, Karamitopoulou E, Gilderman T, Esparza LA, Shima Y, Spahn P, French R, Lewis NE, Fisch KM, Sasik R, Rosenthal SB, Kritzik M, Von Hoff D, Han H, Ideker T, Deshpande AJ, Lowy AM, Adams PD, and Reya T
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma metabolism, Animals, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cell Differentiation, Epigenesis, Genetic, Gene Library, Humans, Mice, Mice, Knockout, Mice, SCID, Neoplastic Stem Cells cytology, Nuclear Receptor Subfamily 1, Group F, Member 3 antagonists & inhibitors, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, RNA Interference, RNA, Small Interfering metabolism, Receptors, G-Protein-Coupled antagonists & inhibitors, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Receptors, Interleukin-10 antagonists & inhibitors, Receptors, Interleukin-10 genetics, Receptors, Interleukin-10 metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transcriptome, Tumor Cells, Cultured, Adenocarcinoma pathology, Neoplastic Stem Cells metabolism, Pancreatic Neoplasms pathology
- 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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