Abstract Background Peroxisome proliferator-activated receptor delta (PPARδ) is upregulated in many types of human cancers, including gastric adenocarcinoma (GAC). Elevated PPARδ expression correlates positively with GAC grade and stage, and negatively with patient survival. Overexpression of PPARδ in villin-positive gastric progenitor cells (VGPCs) has been shown to spontaneously induce GAC in villin-PPARδ mice through CCR20/CCR6 axis-mediated remodeling of the gastric tumor microenvironment. Lgr5-positive gastric stem cells (LGSCs), located in the gastric antrum and corpus glands, have also been widely studied for their role in GAC initiation and progression. However, whether this PPARδ-driven GAC is specific to particular cell types or models remains largely unknown. Methods A new conditional transgenic PPARδ overexpression mouse line (CAG-LSL-PPARδ) was generated and subsequently crossed with villin-Cre or Lgr5-EGFP-IRES-CreERT2 mice (Lgr5-CreERT2) to generate CAG-LSL-PPARδ; villin-Cre (PPARδvillin-cre) or CAG-LSL-PPARδ; Lgr5-CreERT2 (PPARδlgr5-creERT2) mice, in which PPARδ was overexpressed in VGPCs or LGSCs following tamoxifen induction. PPARδvillin-cre mice (n=15) and their controls (villin-Cre, n=12) were followed up until 45 weeks of age, whereas PPARδlgr5-creERT2 (n=16) and their controls (Lgr5-CreERT2, n=14) were observed for 45 weeks post-tamoxifen induction. Additionally, villin-PPARδ mice were bred with CCR6 knockout (CCR6-KO) mice to generate villin-PPARδ; CCR6-KO mice, which along with villin-PPARδ mice, were monitored until 35 weeks of age. All mice were evaluated for tumor multiplicity and subjected to histopathological examination. Results Gastric hyperplasia and/or low-grade dysplasia occurred in the corpus of 100% of PPARδvillin-cre and PPARδlgr5-creERT mice. High-grade dysplasia and/or locally invasive GAC were found in the corpus of 27% (4/15) of PPARδvillin-cre, in both the corpus and antrum of 13% (2/16), and in the corpus of 19% (3/16) of PPARδlgr5-creERT2, whereas none of the control mice developed these lesions. Chronic inflammation was present in gastric lesions and positively correlated with tumor progression from hyperplasia to locally invasive GAC. CCR6 KO markedly suppressed PPARδ overexpression in VGPCs-induced gastric inflammation and tumorigenesis. Conclusions PPARδ overexpression in both VGPCs and LGSCs induces chronic gastric inflammation and tumor formation. PPARδ, CCR6, VGPCs, and LGSCs may represent potential therapeutic targets for GAC. Citation Format: Xiangsheng Zuo, Yi Liu, DAOYAN WEI, James C. Yao, Imad Shureiqi. PPARδ overexpression drives transformation of multiple gastric progenitor and stem cells and tumorigenesis in mice abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 824.
Zuo et al. (Fri,) studied this question.