A multiscale map of the stem cell state in pancreatic adenocarcinoma

Therapy resistance and resultant relapse remain key challenges in pancreatic cancer, and are in part driven by the inherent heterogeneity of the tumor that prevents effective targeting of all malignant cells. Here we utilized a combination of RNA-seq, ChIP-seq and genome-wide CRISPR screening to systematically map the dependencies of pancreatic cancer stem cells, highly drug resistant cells that are also enriched in the capacity to drive progression 1-4 . Integration of these data revealed an unexpected role for immuno-regulatory genes in stem cell self-renewal and maintenance in KP f/f C tumors. In particular, Retinoic acid receptor-related orphan receptor gamma (ROR g) , a nuclear hormone receptor known for its role in inflammatory cytokine responses and T cell differentiation 5,6 , emerged as a key regulator of stem cells. ROR g expression rose with pancreatic cancer progression, and its inhibition via genetic approaches or small molecule inhibitors led to a striking defect in pancreatic cancer growth in vitro and in vivo. Collectively, these data reveal an unexpected co-option of immuno-regulatory signals by pancreatic cancer stem cells, and suggest that therapeutics currently being used for autoimmune indications should be considered for treatment of pancreatic cancer.