Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ.
Yi LiuYasunori DeguchiDaoyan WeiFuyao LiuMicheline J MoussalliEriko DeguchiDonghui LiHuamin WangLovie Ann ValentinJennifer K ColbyJing WangXiaofeng ZhengHaoqiang YingMihai GageaBaoan JiJiaqi ShiJames C YaoXiangsheng ZuoImad ShureiqiPublished in: Nature communications (2022)
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 KRAS G12D (KRAS mu ) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This PPARδ activation induces KRAS mu 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.
Keyphrases
- wild type
- insulin resistance
- high fat diet
- fatty acid
- adipose tissue
- high grade
- high fat diet induced
- stem cells
- skeletal muscle
- metabolic syndrome
- type diabetes
- induced apoptosis
- risk assessment
- liver fibrosis
- electronic health record
- regulatory t cells
- signaling pathway
- binding protein
- immune response
- genetic diversity