PPAR-δ Orchestrates a Pro-metastatic 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 employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ 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 PPAR-δ. Specifically, PPAR-δ 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 pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.