Abstract 2520: Blocking muscle wasting via deletion of the muscle specific E3 ligase, MuRF1, impedes pancreatic tumor growth

Abstract Pancreatic cancer-induced muscle atrophy is a debilitating condition that contributes to a deterioration in physical function and reduced quality of life, often complicates or precludes cancer treatment, and strongly predicts early mortality from cancer. A pharmacological therapy for this atrophy does not exist, in part because of an incomplete understanding of the molecular mechanisms which are causative in the condition. We recently identified that Trim63/MuRF1 is elevated in skeletal myonuclei from cachectic mice and people with pancreatic ductal adenocarcinoma (PDAC) compared to non-cancer controls. MuRF1 is an E3 ubiquitin ligase, specific to striated muscle that targets proteins for degradation. Based on this finding, we investigated the requirement of MuRF1 for PDAC-induced muscle atrophy. Murine KPC cells (or saline) were injected orthotopically into the pancreas of WT and MuRF1 KO mice, and tissues harvested at several time points throughout tumor progression. WT KPC mice showed loss of tumor-free body mass and muscle mass by day 12, and reached experimental endpoint on day 16, defined by significant body wasting in combination with a body condition score ≤2. At endpoint, WT KPC mice showed significant muscle wasting (-8-17%), muscle weakness (-32-46%), fat wasting (-71%) and splenomegaly (+100%) and had a mean tumor mass of 1.9 ± 0.5 g. At this same timepoint (day 16), MuRF1 KO KPC mice were completely protected from body, muscle and fat wasting, with KPC tumors in MuRF1 KO mice 84% smaller than in WT mice. We therefore tracked an additional cohort of MuRF1 KO KPC mice until their tumors reached a comparable size to that of WT mice at their endpoint which, on average, was reached on day 32. Despite having comparable tumor mass at this time point, MuRF1 KO mice remained protected from body, muscle and fat wasting, and were spared from muscle weakness. Using ubiquitin proteomics in muscle, we found that MuRF1 was responsible for the ubiquitination of multiple cytoskeletal and contractile proteins—whose proteolytic degradation into amino acids may contribute to myofiber atrophy and help fuel tumor growth. To explore the impact of MuRF1 deletion on tumor metabolism we conducted global metabolomic profiling of KPC tumors from WT mice on day 16, and from MuRF1 KO mice on day 16 and at matched tumor size. Overall, these analyses revealed an accumulation of metabolites in tumors from MuRF1 KO mice, including glucose, amino acids and amino acid derivatives, suggesting that pancreatic tumors in mice spared from muscle wasting may be less metabolically active. In summary, these combined findings demonstrate that MuRF1 is required for KPC-induced skeletal muscle catabolism, whose deletion impinges on normal tumor metabolism and delays tumor growth. Citation Format: Daria Neyroud, Orlando Laitano, Christopher Lopez, David W. Hammers, H Lee Sweeney, Glenn A. Walter, Sarah M. Judge, Andrew R. Judge. Blocking muscle wasting via deletion of the muscle specific E3 ligase, MuRF1, impedes pancreatic tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2520.