Cachexia is a condition characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments, and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development of treatments to improve quality of life and enhance survival of cancer patients.
Aim 3 of the parent RO1, aimed to identify a gene signature that associates with muscle wasting in cancer patients and tumor-bearing mice. To do this, we conducted genome-wide transcriptomic analyses of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), who have one of the highest rates of cachexia, and in multiple models of cancer cachexia. Included among the models studied was the patient derived xenograft (PDX) model, in which tumors resected from PDAC patients are directly sutured to the mouse pancreas, where they propagate and induce cachexia. From these studies we identified genes commonly changed (?1.5 ? fold change ? 1.5, q ? 0.01) in skeletal muscle from cachectic cancer patients, and in 9 different cohorts of mice in response to tumor burden, including 5 different PDAC-PDX cohorts created from 5 PDAC patients, the C26 model, and mice injected orthotopically with various pancreatic cancer cell lines, including human L3.6pl and Panc-1 cells and mouse KPC cells. One gene commonly changed across these 9 mouse models and in patients was Trim63 (MuRF1), a well-established regulator of skeletal muscle wasting in various physiological and pathophysiological conditions. Despite this, the role of MuRF1 in tumor-induced muscle atrophy is not known. We therefore conducted a preliminary experiment to test this role using MuRF1 knockout (MuRF1-/-) mice, hypothesizing that deletion of MuRF1 would attenuate tumor-induced atrophy. To our surprise, our findings were far more striking. Knockout of MuRF1, which is muscle-specific, completely prevented the cancer-induced loss of muscle mass and fat mass, significantly delayed tumor growth (by nearly the rate of growth in WT mice) and more than doubled survival. Importantly, the complete preservation of muscle and fat mass in MuRF1-/- mice was not confounded by differences in tumor size, as these tissue measurements were made at time points in which KPC tumors in MuRF1-/- mice were equal in size to that reached in WT mice. These striking preliminary findings provide an incredible foundation on which we propose to build through this STAR Program award. Our proposed studies will a) identify the proteins which are ubiquitinated and degraded in skeletal muscle in response to tumor burden, that require MuRF1 and, b) determine the extent to which loss of MuRF1 in tumor bearing mice: i) alters the metabolome in muscle, fat, tumor and serum; ii) alters the tumor- associated dysregulation of circulating growth factors/cytokines in the circulation which associate with the cachectic phenotype and iii) attenuates muscle weakness. Findings from these studies will provide a wealth of new data to facilitate the continued expansion of our research program.

Public Health Relevance

Skeletal muscle wasting and weakness are associated with several cancers and significantly impact physical function, quality of life, and a patient?s ability to withstand aggressive conventional treatments for the cancer. We have identified a gene signature in skeletal muscle that is associated with muscle wasting in pancreatic cancer patients and nine pre-clinical models of cancer cachexia. In the current work we will study the role of Trim63, a gene within this signature, to establish its role in cancer cachexia, including muscle and fat wasting and metabolism, tumor growth and metabolism, and survival.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Boyce, Amanda T
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University of Florida
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Schools of Public Health
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Kandarian, Susan C; Nosacka, Rachel L; Delitto, Andrea E et al. (2018) Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice. J Cachexia Sarcopenia Muscle 9:1109-1120
Murphy, Kate T; Hossain, Mohammed I; Swiderski, Kristy et al. (2018) Mas receptor activation slows tumor growth and attenuates muscle wasting in cancer. Cancer Res :
Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E et al. (2017) Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia. Oncotarget 8:1177-1189
Ahn, Bumsoo; Beharry, Adam W; Frye, Gregory S et al. (2015) NAD(P)H oxidase subunit p47phox is elevated, and p47phox knockout prevents diaphragm contractile dysfunction in heart failure. Am J Physiol Lung Cell Mol Physiol 309:L497-505
Ryder, Daniel J; Judge, Sarah M; Beharry, Adam W et al. (2015) Identification of the Acetylation and Ubiquitin-Modified Proteome during the Progression of Skeletal Muscle Atrophy. PLoS One 10:e0136247
Beharry, Adam W; Judge, Andrew R (2015) Differential expression of HDAC and HAT genes in atrophying skeletal muscle. Muscle Nerve 52:1098-101
Reid, Michael B; Judge, Andrew R; Bodine, Sue C (2014) Rebuttal from Michael B. Reid, Andrew R. Judge and Sue C. Bodine. J Physiol 592:5351
Reid, Michael B; Judge, Andrew R; Bodine, Sue C (2014) CrossTalk opposing view: The dominant mechanism causing disuse muscle atrophy is proteolysis. J Physiol 592:5345-7
Beharry, Adam W; Sandesara, Pooja B; Roberts, Brandon M et al. (2014) HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy. J Cell Sci 127:1441-53
Judge, Sarah M; Wu, Chia-Ling; Beharry, Adam W et al. (2014) Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia. BMC Cancer 14:997

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