PPARδ Orchestrates a Prometastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.

The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells use various adaptive mechanisms that may represent therapeutic targets. In this study, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPARδ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPARδ. Specifically, PPARδ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacologic inhibition of PPARδ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPARδ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a prometastatic phenotype in PDAC, suggesting that PPARδ inhibition could serve as a therapeutic strategy to combat PDAC progression. SIGNIFICANCE: Nutrient starvation and microenvironmental signals activate PPARδ in pancreatic cancer to support survival and metastasis by promoting metabolic plasticity and invasiveness, providing a strong rationale for developing PPARδ-targeted therapies for pancreatic cancer.