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.
Cachexia is a syndrome of cancer that promotes severe weight loss and is a major contributor to patient morbidity and mortality. It is often written that cachexia is observed in a majority of cancers, and quite striking, that 20-25% of all cancer deaths is due to cachexia rather than directly from the tumor burden. The National Cancer Institute has recognized the severity of this syndrome and what it means to a patient's depreciating quality of life, and therefore has targeted cachexia as one of their 24 provocative research questions to address. Although the main efforts in cachexia research over the past decades have focused on events and pathways that regulate muscle wasting from within the myofiber, this proposal will explore the mechanisms and relevance of events that take place outside the fiber and within the muscle microenvironment, involving the dysregulation of muscle stem cells and their inability to repair muscle that has been injured by a developing tumor. We believe findings from these studies will significantly expand our understanding of the underlying causes of cancer cachexia and help identify new mechanisms that can be therapeutically targeted to improve cachexia treatment and cancer care.
|He, Wei A; Calore, Federica; Londhe, Priya et al. (2014) Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7. Proc Natl Acad Sci U S A 111:4525-9|