[HTML][HTML] Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming
A Velez-Delgado, KL Donahue, KL Brown, W Du… - Cellular and molecular …, 2022 - Elsevier
A Velez-Delgado, KL Donahue, KL Brown, W Du, V Irizarry-Negron, RE Menjivar…
Cellular and molecular gastroenterology and hepatology, 2022•ElsevierBackground & Aims Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation
of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse
models of the disease. Although 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. Methods Using a genetically engineered mouse
model of inducible and reversible oncogenic Kras expression and a combination of …
of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse
models of the disease. Although 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. Methods Using a genetically engineered mouse
model of inducible and reversible oncogenic Kras expression and a combination of …
Background & Aims
Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although 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.
Methods
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 studied the effect of oncogenic KRAS in the tumor microenvironment.
Results
We have discovered that non–cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair.
Conclusions
Our study provides fundamental 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.
Elsevier
