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

Abstract

SummaryIn pancreatic cancer, emerging evidence suggests that PPAR-δ overexpression is associated with tumor progression and metastasis, but a mechanistic link is still missing. Here we now show that PPAR-δ acts as the integrating upstream regulator for the metabolic rewiring, which is preceding the subsequent initiation of an invasive/metastatic program. Specifically, paracrine and metabolic cues regularly found in the metastasis-promoting tumor stroma consistently enhance, via induction of PPAR-δ activity, the glycolytic capacity and reserve of pancreatic cancer cells, respectively, accompanied by decreased mitochondrial oxygen consumption. Consequently, genetic or pharmacological inhibition of PPAR-δ results in reduced invasiveness and metastasis. Mechanistically, PPAR-δ acts by shifting the MYC/PGC1A balance towards MYC, enhancing metabolic plasticity. Targeting MYC similarly prevents the metabolic switch and subsequent initiation of invasiveness. Therefore, our data demonstrate that PPAR-δ is a key initiator for the metabolic reprogramming in pancreatic cancer, thereby acting as a checkpoint for the phenotypic change towards invasiveness. These findings provide compelling evidence for a novel treatment strategy to combat pancreatic cancer progression.