Abstract 3038: PPARδ promotes gastric adenocarcinoma carcinogenesis by enhancing ZBP1-induced necroptosis and inflammation and fostering gastric tumor immunosuppressive microenvironment

Abstract

Abstract Overexpression of peroxisome proliferator-activated receptor delta (PPARδ) in villin-positive gastric progenitor cells (VGPCs) has been demonstrated to spontaneously induce gastric adenocarcinoma (GAC) in mice. PPARδ is upregulated in human GAC tissues, and its expression level is positively associated with human GAC grades and stages. However, the potential for targeting this tumorigenic effect of PPARδ, along with the underlying molecular mechanisms, remains elusive. In this study, we investigated the impact of PPARδ genetic deletion/loss of function in VGPCs on Helicobacter felis (H. felis)-induced GAC carcinogenesis by orally exposing the mice carrying wild-type (WT) PPARδ or genetically deleted PPARδ in VGPCs to H. felis infection. We also examined the effect of PPARδ inhibition by its specific antagonist, GSK3787, on PPARδ-induced GAC carcinogenesis in mice. Furthermore, we conducted RNA-seq for transcriptomic profiling analysis and validated the results through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on the gastric tissues of those mice and the mice with WT PPARδ or PPARδ overexpression in VGPCs at ages 10, 25 and 55 weeks. We found that 1) PPARδ genetic deletion in VGPCs significantly inhibited H. felis-induced gastric chronic inflammation and GAC carcinogenesis; GSK3787 significantly suppressed PPARδ-induced GAC carcinogenesis in mice; 2) PPARδ overexpression in VGPCs significantly enhanced while PPARδ genetic deletion in VGPCs significantly inhibited ZBP1-induced necroptosis and the related inflammatory signaling pathways such as interferon-gamma signaling, IL6-JAK-STAT3 signaling, and IL2-STAT5 signaling evidenced by gene set enrichment analysis of RNA-seq data, which were further validated by qRT-PCR; and 3) PPARδ overexpression in VGPCs markedly increased the expression of CCL20 in gastric epithelial cells of the mice before (age 10 weeks) and after GAC initiation and progression (age 25 weeks-early stage GAC and age 55 weeks-late stage GAC), and gastric infiltrations of CCR6+ myeloid-derived suppressor cells and CCR6+ tumor-associated macrophages, thereby creating a gastric tumor immunosuppressive microenvironment. In contrast, PPARδ genetic deletion in VGPCs or the administration of GSK3787 diet significantly reversed this PPARδ-induced immune suppression in mice. In conclusion, our findings highlight the pivotal role of PPARδ in VGPCs as a key host factor in GAC carcinogenesis, especially in individuals exposed to chronic H. pylori infection that could lead to an upregulation of PPARδ expression. This suggests that targeting PPARδ signaling could be a novel therapeutic approach for GAC prevention and therapy. Citation Format: Yi Liu, Daoyan Wei, Lily Wang, James C. Yao, Imad Shureiqi, Xiangsheng Zuo. PPARδ promotes gastric adenocarcinoma carcinogenesis by enhancing ZBP1-induced necroptosis and inflammation and fostering gastric tumor immunosuppressive microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3038.