A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma

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; and Tannishtha Reya
Cell. 2019 Mar;177, 1-15. PDF |

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 (RORg), 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 RORg 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.