| First Author | Liu Y | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 2665 |
| PubMed ID | 35562376 | Mgi Jnum | J:324554 |
| Mgi Id | MGI:7280247 | Doi | 10.1038/s41467-022-30392-7 |
| Citation | Liu Y, et al. (2022) Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARdelta. Nat Commun 13(1):2665 |
| abstractText | 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 (PPARdelta), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARdelta ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARdelta ligand) in mutant KRAS(G12D) (KRAS(mu)) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This PPARdelta 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 PPARdelta signaling as a potential molecular target to prevent PDAC development in subjects harboring PanINs. |
