Abstract A045: Pancreatic cancer-associated systemic nutrient starvation elevates autophagic proteolysis in the muscle

Abstract

The pancreas regulates whole-body metabolism through its exocrine and endocrine functions. In pancreatic ductal adenocarcinoma (PDAC), tumor-driven exocrine dysfunction contributes to systemic nutrient depletion, but its role in muscle wasting remains poorly understood. Using genetically engineered mouse models (GEMMs) of PDAC and orthotopic implantation of murine PDAC cells, we observed early disease features including hypoglycemia, elevated circulating branched-chain amino acids, and loss of muscle and fat mass. Skeletal muscle from tumor-bearing mice exhibited suppressed mTORC1 signaling, reduced protein synthesis, activated AMPK signaling, and elevation of Foxo1/Foxo3a-driven lysosome-autophagy pathways, leading to muscle proteolysis. Loss-of pancreatic acinar cells impaired exocrine function, whereas dietary enzyme supplementation rescued protein digestion and restored muscle mass. Muscle-specific deletion of Atg7 reduced muscle wasting, slowed tumor growth, and improved survival. Stable isotope tracing using a 15N-labeled Spirulina diet revealed that amino acids derived from host muscle were utilized by tumors and other tissues. Notably, in mice with impaired muscle autophagy, a high elemental amino acid diet increased mortality, while a low elemental amino acid diet improved survival—suggesting that excess nutrients may fuel tumor growth when muscle catabolism is blocked. Together, these findings indicate that PDAC-induced exocrine insufficiency triggers a starvation-like state that promotes muscle wasting through autophagy, ultimately supporting tumor and host tissue metabolism. Citation Format: Yetiş Gültekin, Sharanya Sivanand, Kian Moritz Eghbalian, Anna Marie Barbeau, Keene Abbott, George Eng, Tori Tavernier, Brian Do, Elif Ozcelik, Sabrina Hu, Tenzin Kunchok, Millenia Waite, Daniel A. Sharygin, Yigit Kaan Kizlier, Will Freed-Pastor, Tyler Jacks Omer Yilmaz, Jonathan Nowak, Brian Wolpin, Matthew G. Vander Heiden. Pancreatic cancer-associated systemic nutrient starvation elevates autophagic proteolysis in the muscle [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A045.