Ppard Is Essential in Acceleration of Pancreatic Ductal Adenocarcinoma Development by High-Fat Diet in MutantKrasMice

Abstract

Pro-obesity high-fat diet is linked with an increased incidence of pancreatic cancers, but the molecular underpinnings of this association remain poorly understood. Here, we report that PPARD is upregulated in pancreatic intraepithelial neoplasia lesions (PanINs) at early stages of pancreatic tumorigenesis in humans and mutant Kras mice. Transgenic overexpression of Ppard in pancreatic epithelial cells drastically accelerates the development and progression of pancreatic ductal adenocarcinoma in mutant Kras mice when activated by feeding the mice with a high-fat diet or a diet containing GW501516 (50 mg/kg), a selective PPARD agonist. In contrast, pancreatic Ppard genetic deletion significantly suppressed the promotion of pancreatic tumorigenesis by these diets. Mechanistically, we found that this Ppard hyperactivation in pancreatic epithelial cells of mutant Kras mice increased production of chemokines and cytokines (e.g., CcI2, CcI4-5, CxcI5 and II6), leading to the robustly increased recruitment of myeloid-derived suppressor cells and macrophages into pancreata, which fostered an immune suppressive microenvironment and subsequently accelerated pancreatic ductal adenocarcinoma development and progression. Our findings demonstrate that PPARD plays an essential role in the promotion of pancreatic tumorigenesis by a high-fat diet. Targeted inhibition of PPARD activation is a potential interventive strategy for pancreatic cancer prevention and therapy.

PPAR-delta acts as a metabolic master checkpoint for metastasis in pancreatic cancer

“…Finally, we found that genetic or pharmacological targeting of PPAR-δ inhibited tumor aggressiveness and metastasis in vitro and in vivo (Figure 8). These data are in line with previous reports for murine PDAC models showing that Ppard knock-down strongly decreased tumorigenesis mouse melanoma cells (Zuo et al, 2017), and Ppard knockout inhibited tumor progression in KC mice on a high-fat diet (Liu et al, 2020). Taken together, accumulating data now strongly support the concept that PPAR-δ inhibition reduces the MYC/PGC1A ratio and thereby diminishes PDAC progression and metastasis.…”

“…Even more importantly, poor patient outcome, including reduced metastasis-free survival correlated with PPARD expression in various cancer types (Abdollahi et al, 2007;Zuo et al, 2017). However, while accumulating evidence suggest that PPAR-δ also promotes tumor progression and metastasis in PDAC (Liu et al, 2020;Sanford-Crane et al, 2020;Zuo et al, 2017), other reports have questioned these finding (Coleman et al, 2013;Smith et al, 2016).…”