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-seq, ChIP-seq, and genome-wide CRISPR analysis to map 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 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. Pancreatic cancer stem cells co-opt immunoregulatory pathways, a vulnerability that could be exploited therapeutically by agents currently in trials for autoimmune diseases