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

Autor: Liu Y; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Deguchi Y; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Wei D; Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Liu F; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Moussalli MJ; Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Rogel Cancer Center and Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, 48109, USA., Deguchi E; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Li D; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Wang H; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Valentin LA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Colby JK; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Wang J; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Zheng X; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Ying H; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Gagea M; Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Ji B; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA., Shi J; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA., Yao JC; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Zuo X; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. xzuo@mdanderson.org., Shureiqi I; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ishureiq@med.umich.edu.; Rogel Cancer Center and Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, 48109, USA. ishureiq@med.umich.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 May 13; Vol. 13 (1), pp. 2665. Date of Electronic Publication: 2022 May 13.
DOI: 10.1038/s41467-022-30392-7
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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