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

作者：Beatriz Parejo-Alonso, David Barneda, Sara Maria David Trabulo, Sarah Courtois, Sara Compte-Sancerni, Jelena Zurkovic, Laura Ruíz-Cañas, Quan Zheng, Jiajia Tang, Matthias M. Gaida, Ulf Schmitz, Pilar Irún, Laure Penin-Peyta, Shanthini Mary Crusz, Petra Jagušt, Pilar Espiau-Romera, Alba Royo-García, Andrés Gordo-Ortiz, Mariia Yuneva, Meng‐Lay Lin, Shenghui Huang, Ming-Hsin Yang, Ángel Lanas, Bruno Sáinz, Christoph Thiele, Christopher Heeschen, Patricia Sancho · 年份：2025 · DOI：10.1158/0008-5472.c.8012072 · 被引用次数：1 · 研究领域：Peroxisome Proliferator-Activated Receptors、Cancer, Lipids, and Metabolism、Cancer, Hypoxia, and Metabolism

<div>AbstractThe 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.</p&gt...