Delineating the contribution of muscle wasting to tumor progression

ABSTRACT Skeletal muscle wasting affects up to 80% of patients with advanced cancer and directly impacts surgical prognosis, chemotherapeutic response, morbidity, mortality, and quality of life. While considerable effort has gone into understanding how tumors (and the host response to tumors) contribute to the etiology of cancer cachexia, relatively little is known about how the cachectic state in turn influences tumor dynamics. Our long- term goal is to develop a better understanding of reciprocal tumor-host interactions to approach therapeutic development more holistically in cancer patients. We present preliminary data highlighting the role of muscle wasting with respect to tumor progression. First, we show that mice genetically engineered to resist muscle wasting exhibit enhanced survival and slower tumor growth compared to matched control mice subjected to the same tumor transplantation protocol. Second, preliminary analyses of tumors isolated from these mice point to significant differences in cell type composition and gene expression as a function of muscle wasting. Third, we observe a divergent/unique secretome associated with ongoing myofiber atrophy. This proposal builds on these exciting findings and will address the central hypothesis that skeletal muscle wasting actively promotes tumor progression. In this proposal we will 1) detail tumor progression in the presence/absence of muscle wasting and determine if wasting prevention and intervention is sufficient to augment tumor growth, and 2) interrogate the skeletal muscle secretome to better understand the fate, composition, and function of catabolic muscle breakdown products. Together, we anticipate this work being a significant and innovative step towards better understanding the dynamic and complex relationship between tumors and host tissues, such as skeletal muscle.