Paper

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Brown, Kristee L, Steele, Nina G, Lasse-Opsahl, Emily L, Lyssiotis, Costas A, Donahue, Katelyn L, Kemp, Samantha B, Velez-Delgado, Ashley, Lazarus, Jenny, Rao, Arvind, Kerk, Samuel A, Lima, Fatima, Frankel, Timothy L, Irizarry-Negron, Valerie, Bednar, Filip, Crawford, Howard C, Sirihorachai, Veerin R, Bollamplly, Murali, Yan, Wei, Stephanie The, Zhang, Yaqing, Menjivar, Rosa E, Du, Wenting, Marina Pasca Di Magliano

2021

Overview

Oncogenic KRAS is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. While the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single cell RNA sequencing, we have discovered that non-cell autonomous (i.e., extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, mediating the polarization and function of pro-tumorigenic myeloid cells while also preventing tissue repair. Our study provides fundamental new knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Animal models / Cancer Biology / Cytometry / Fibroblasts / Gene expression / Genetic engineering / Inflammation / K-Ras protein / Myeloid cells / Pancreatic cancer / Stroma / Tumor microenvironment / Tumorigenesis