TY - JOUR T1 - Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation JF - bioRxiv DO - 10.1101/833046 SP - 833046 AU - Tim D.D. Somerville AU - Giulia Biffi AU - Juliane Daßler-Plenker AU - Koji Miyabayashi AU - Yali Xu AU - Diogo Maia-Silva AU - Olaf Klingbeil AU - Osama E. Demerdash AU - Mikala Egeblad AU - David A. Tuveson AU - Christopher R. Vakoc Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/06/833046.abstract N2 - A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans-differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63-dependent manner. These non cell-autonomous effects occur, at least in part, through TP63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment. ER -