(PQD6) Muscle stem cells and cancer cachexia

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DESCRIPTION (provided by applicant): Cachexia is a debilitating syndrome of cancer that results in severe weight loss due to the depletion of skeletal muscle. Patients with cachexia have poor prognosis and a depreciating quality of life. This syndrome is prevalent in a majority of cancers, but is especially relevant for pancreatic cancer where estimates suggest that 85% of patients experience significant weight loss. Managing cachexia will likely hinge on our abilities t better understand the underlying mechanisms driving tumor-induced muscle wasting, and with this knowledge an increasing number of therapeutic targets can be identified and translated to the clinic. This notion is the basis of our proposal and is in line with NCI's provocative research question on cancer cachexia to elucidate mechanisms that initiate cachexia in patients and find ways to target these mechanisms to extend lifespan and quality of life. Our recent efforts have centered on events that occur outside the myofiber and within the muscle environment. We find that tumors elicit an injury response that initiates muscle stem cell activation and differentiatio to repair damaged fibers, but this differentiation program is blocked due to deregulation of the self-renewing factor, Pax7. The goal of this application is to explore the hypothesis that events occurring outside the myofiber are not simply consequences of a developing cancer, but instead causal factors that contribute to the pathology of cachexia. Towards this goal we seek to perform the following two specific aims: 1) Characterize the myogenic stem cells that contribute to muscle wasting; and 2) Elucidate the role and mechanism of Pax7 deregulation in cancer cachexia. Achieving this goal will not only provide insight into the mechanisms and therapeutic targets of muscle wasting in cancer, but will also broaden an area of cachexia research that, to this point, has been underexplored.