A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.

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.

• Authors: Nikki K Lytle, L Paige Ferguson, Nirakar Rajbhandari, Kathryn Gilroy, Raymond G Fox, Anagha Deshpande, Christian M Schürch, Michael Hamilton, Neil Robertson, Wei Lin, Pawan Noel, Martin Wartenberg, Inti Zlobec, Micha Eichmann, José A Galván, Eva Karamitopoulou, Tami Gilderman, Lourdes Adriana Esparza, Yutaka Shima, Philipp Spahn, Randall French, Nathan E Lewis, Kathleen M Fisch, Roman Sasik, Sara Brin Rosenthal, Marcie Kritzik, Daniel Von Hoff, Haiyong Han, Trey Ideker, Aniruddha J Deshpande, Andrew M Lowy, Peter D Adams, Tannishtha Reya
• Journal: Cell (Cell) Vol. 177 Issue 3 Pg. 572-586.e22 (04 18 2019) ISSN: 1097-4172 [Electronic] United States
• PMID: 30955884 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cell Adhesion Molecules
• Nuclear Receptor Subfamily 1, Group F, Member 3
• RNA, Small Interfering
• Receptors, G-Protein-Coupled
• Receptors, Interleukin-10

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Differentiation
• Epigenesis, Genetic
• Gene Library
• Humans
• Mice
• Mice, Knockout
• Mice, SCID
• Neoplastic Stem Cells (cytology, metabolism)
• Nuclear Receptor Subfamily 1, Group F, Member 3 (antagonists & inhibitors, genetics, metabolism)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, genetics, metabolism)
• Receptors, Interleukin-10 (antagonists & inhibitors, genetics, metabolism)
• T-Lymphocytes (cytology, immunology, metabolism)
• Transcriptome
• Tumor Cells, Cultured