Abstract 3846: BNIP3-dependent muscle atrophy in cancer cachexia promotes PDAC progression

Abstract Cancer cachexia is a debilitating effect of several human cancers, including pancreatic ductal adenocarcinoma (PDAC), that involves involuntary body weight loss due to wasting of skeletal muscle (with or without loss of adipose tissue). Cancer cachexia negatively affects the long-term survival of cancer patients, partly due to reduced tolerance of and response to therapy, and increased mortality due to cardiac and respiratory failure. Here, we present new data demonstrating a role for the mitochondrial cargo receptor BNIP3 in driving muscle atrophy during cachexia caused by PDAC in genetically engineered mouse models. Muscle-specific deletion of BNIP3 in CB mice (Mck-Cre;Bnip3fl/fl) inhibited muscle atrophy in the KPF (FSF-KRasG12D;p53 Frt/+;p48-FlpO) mouse model of PDAC such that skeletal muscle in age-matched compound KPFCB mice (FSF-KRasG12D;p53 Frt/+;p48-FlpO; Mck-Cre;Bnip3fl/fl) exhibited increased weight, increased myofiber cross-sectional area, and decreased expression of muscle atrogenes MuRF1 and Atrogin1, compared to KPF mice. Orthotopic injection of KPF and KPC PDAC lines and sub-cutaneous injection of LLC lung tumor lines similarly revealed key differences in muscle atrophy between WT and CB mice. The sustained health of myofibers in KPFCB mice compared to KPF mice was associated with increased mitochondrial mass, increased mTOR activity, and decreased autophagy markers. In addition to limiting muscle atrophy, loss of BNIP3 in muscle attenuated PDAC tumorigenesis with tumors exhibiting delayed progression from pre-malignant pancreatic intra-epithelial neoplasia (PanINs) to PDAC, and muscle-specific loss of BNIP3 extended lifespan of KPF mice. These findings indicate that degradation of muscle driven by BNIP3-dependent mitophagy is “feeding” the PDAC tumor via factors circulating in plasma. Steady state metabolomics revealed that purines were amongst the most down-regulated metabolites in muscle and plasma of cachectic mice consistent with a model in which BNIP3-dependent mitophagy in muscle is limiting 1C metabolism due to decreased mitochondrial mass. Together, our findings identify BNIP3 as a molecular target in muscle for therapeutic intervention to limit both cancer cachexia and tumor progression. Citation Format: Alexandra Sophia Ware, Elizabeth C. Foster, Kay F. Macleod. BNIP3-dependent muscle atrophy in cancer cachexia promotes PDAC progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3846.