A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma

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From: Cell(Vol. 177, Issue 3)
Publisher: Elsevier B.V.
Document Type: Report
Length: 577 words

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Keywords stem cells; Musashi; Msi; cancer stem cells; pancreatic cancer; cancer; PDAC; RORg; immune; cytokines Highlights * Map of PDAC dependencies using RNA-seq, ChIP-seq, and genome-wide CRISPR screening * Expression and direct utilization of cytokine and immune signals in PDAC stem cells * Nuclear hormone receptor ROR[gamma] regulates mouse and human pancreatic cancer * Pharmacologic blockade of ROR[gamma] reduces tumor burden and improves survival Summary 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 (ROR[gamma]), 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 ROR[gamma] 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. Author Affiliation: (1) Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA (2) Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA (3) Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK (4) Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA (5) Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, USA (6) Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA (7) Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland (8) Department of Pediatrics and the Novo Nordisk Foundation Center for Biosustainability, University of California, San Diego School of Medicine, La Jolla, CA, USA (9) Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA (10) Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA (11) Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA (12) Division of Surgical Oncology, Department of Surgery, University of California, San Diego School of Medicine, La Jolla, CA, USA * Corresponding author Article History: Received 30 August 2018; Revised 18 January 2019; Accepted 4 March 2019 (miscellaneous) Published: April 4, 2019 (footnote)13 These authors contributed equally (footnote)14 Lead Contact Byline: Nikki K. Lytle (1,2,13), L. Paige Ferguson (1,2,13), Nirakar Rajbhandari (1,2), Kathryn Gilroy (3), Raymond G. Fox (1,2), Anagha Deshpande (4), Christian M. Schurch (5), Michael Hamilton (1,2), Neil Robertson (3), Wei Lin (6), Pawan Noel (6), Martin Wartenberg (7), Inti Zlobec (7), Micha Eichmann (7), Jose A. Galvan (7), Eva Karamitopoulou (7), Tami Gilderman (1,2), Lourdes Adriana Esparza (1,2), Yutaka Shima (1,2), Philipp Spahn (8), Randall French (9), Nathan E. Lewis (8), Kathleen M. Fisch (10), Roman Sasik (10), Sara Brin Rosenthal (10), Marcie Kritzik (1,2), Daniel Von Hoff (6), Haiyong Han (6), Trey Ideker (9,11), Aniruddha J. Deshpande (4), Andrew M. Lowy (9,12), Peter D. Adams (3,4), Tannishtha Reya [treya@ucsd.edu] (1,2,9,11,14,*)

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Gale Document Number: GALE|A582867384