Tumor cell-intrinsic p38 MAPK signaling promotes IL1?-mediated stromal inflammation and therapeutic resistance in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a KRAS-driven inflammatory program and a desmoplastic stroma, which contribute to the profoundly chemoresistant phenotype. The tumor stroma contains an abundance of cancer-associated fibroblasts (CAFs), which engage in extensive paracrine crosstalk with tumor cells to perpetuate pro-tumorigenic inflammation. Interleukin-1a (IL1a), a pleiotropic, tumor cell-derived cytokine, plays a critical role in shaping the stromal landscape. We have identified p38 MAPK as a key regulator of IL1a gene expression and utilized single-cell RNA sequencing to study the role of p38 MAPK in PDAC Overall design: Single-cell RNA sequencing of tumors derived from genetically-engineered Ptf1aCre/+; LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice treated with either a p38 MAPK inhibitor (ARRY-614) or control vehicle. For 2.5 weeks, three PKT mice were treated with ARRY-614, and three PKT mice were treated with control vehicle. Upon sacrifice, tumors were harvested and three tumors from each treatment group were pooled for downstream sequencing. Single-cell RNA sequencing was performed using the 10X Genomics platform.