Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ

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 () and Imad Shureiqi ()
Additional contact information
Yi Liu: The University of Texas MD Anderson Cancer Center
Yasunori Deguchi: The University of Texas MD Anderson Cancer Center
Daoyan Wei: The University of Texas MD Anderson Cancer Center
Fuyao Liu: The University of Texas MD Anderson Cancer Center
Micheline J. Moussalli: The University of Texas MD Anderson Cancer Center
Eriko Deguchi: The University of Texas MD Anderson Cancer Center
Donghui Li: The University of Texas MD Anderson Cancer Center
Huamin Wang: The University of Texas MD Anderson Cancer Center
Lovie Ann Valentin: The University of Texas MD Anderson Cancer Center
Jennifer K. Colby: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Xiaofeng Zheng: The University of Texas MD Anderson Cancer Center
Haoqiang Ying: The University of Texas MD Anderson Cancer Center
Mihai Gagea: The University of Texas MD Anderson Cancer Center
Baoan Ji: Mayo Clinic
Jiaqi Shi: University of Michigan
James C. Yao: The University of Texas MD Anderson Cancer Center
Xiangsheng Zuo: The University of Texas MD Anderson Cancer Center
Imad Shureiqi: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30392-7

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