Rapid Acceleration of Kras-Mutant Pancreatic Carcinogenesis via Remodeling of Tumor Immune Microenvironment by PPARδ

Authors

Yi Liu
Yasunori Deguchi
Daoyan Wei
Fuyao Liu
Micheline J Moussalli
Eriko Deguchi
Donghui Li
Huamin Wang
Lovie Ann Valentin
Jennifer K Colby
Jing Wang
Xiaofeng Zheng
Haoqiang Ying
Mihai Gagea
Baoan Ji
Jiaqi Shi
James C Yao
Xiangsheng Zuo
Imad Shureiqi

Publication Date

5-13-2022

Journal

Nature Communications

Abstract

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This PPARδ activation induces KRASmu pancreatic epithelial cells to secrete CCL2, which recruits immunosuppressive macrophages and myeloid-derived suppressor cells into pancreas via the CCL2/CCR2 axis to orchestrate an immunosuppressive tumor microenvironment and subsequently drive PanIN progression to PDAC. Our data identify PPARδ signaling as a potential molecular target to prevent PDAC development in subjects harboring PanINs.

Keywords

Animals, Carcinogenesis, Carcinoma in Situ, Carcinoma, Pancreatic Ductal, Humans, Ligands, Mice, PPAR delta, Pancreas, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment

DOI

10.1038/s41467-022-30392-7

PMID

35562376

PMCID

PMC9106716

PubMedCentral® Posted Date

6-13-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes