Abstract IA-005: Metabolic Stress in Pancreatic Cancer Progression and Therapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) cells depend on glutamine to meet their unique metabolic needs. The elevated consumption of glutamine leads to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression and therapy. We will show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in PDAC cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression. During the development of a pharmacological in vivo system aimed at mimicking glutamine stress, we have serendipitously discovered an approach to profoundly affect PDAC tumor growth and metastasis. We will outline the metabolic mechanisms underlying these effects and discuss additional targeting strategies for PDAC. Citation Format: Cosimo Commisso. Metabolic Stress in Pancreatic Cancer Progression and Therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-005.