A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma

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

doi:10.1016/j.cell.2019.03.010

A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma

Cell. 2019 Apr 18;177(3):572-586.e22. doi: 10.1016/j.cell.2019.03.010. Epub 2019 Apr 4.

Authors

Nikki K Lytle¹, L Paige Ferguson¹, Nirakar Rajbhandari¹, Kathryn Gilroy², Raymond G Fox¹, Anagha Deshpande³, Christian M Schürch⁴, Michael Hamilton¹, Neil Robertson², Wei Lin⁵, Pawan Noel⁵, Martin Wartenberg⁶, Inti Zlobec⁶, Micha Eichmann⁶, José A Galván⁶, Eva Karamitopoulou⁶, Tami Gilderman¹, Lourdes Adriana Esparza¹, Yutaka Shima¹, Philipp Spahn⁷, Randall French⁸, Nathan E Lewis⁷, Kathleen M Fisch⁹, Roman Sasik⁹, Sara Brin Rosenthal⁹, Marcie Kritzik¹, Daniel Von Hoff⁵, Haiyong Han⁵, Trey Ideker¹⁰, Aniruddha J Deshpande³, Andrew M Lowy¹¹, Peter D Adams¹², Tannishtha Reya¹³

Affiliations

¹ Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
² Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.
³ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
⁴ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, USA.
⁵ Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.
⁶ Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
⁷ Department of Pediatrics and the Novo Nordisk Foundation Center for Biosustainability, University of California, San Diego School of Medicine, La Jolla, CA, USA.
⁸ Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA.
⁹ Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
¹⁰ Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
¹¹ Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Division of Surgical Oncology, Department of Surgery, University of California, San Diego School of Medicine, La Jolla, CA, USA.
¹² Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹³ Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA; Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA. Electronic address: treya@ucsd.edu.

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.

Keywords: Msi; Musashi; PDAC; RORg; cancer; cancer stem cells; cytokines; immune; pancreatic cancer; stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
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
Neoplastic Stem Cells / metabolism*
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
Pancreatic Neoplasms / pathology*
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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding