Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma that occurs in children. Current treatment protocols for RMS combine surgery, chemotherapy, and radiation, yet fail to cure 30% of RMS cases. Though heterogeneous in clinical phenotype, all RMS are thought to arise from skeletal muscle precursor cells. The proto-oncogene, c-Met, is deregulated in at least two types of RMS, embryonal and the more aggressive alveolar, and has been identified as a potential target for treating RMS. c-Met encodes a receptor tyrosine kinase. Activation by its ligand, Hepatocyte Growth Factor (HGF), triggers multiple signaling cascades that modulate cell survival, proliferation, and migration of various cultured cell types. In vivo, the HGF/c-MET axis mediates efficient adult liver and skin regeneration in response to injury. Furthermore, this axis is indispensible for the migration and proliferation of appendicular muscle progenitors during embryogenesis. Based on these findings, c-Met likely plays a role in adult muscle stem cells, i.e. satellite cells (SCs), during injury induced skeletal muscle regeneration. In uninjured muscle, quiescent SCs express c-Met. Upon muscle injury, SCs activate to proliferate and become myoblasts (muscle precursor cells) that accumulate at sites of injury where they fuse to form new muscle fibers. c-Met and Hgf are up-regulated in the muscle during this period, suggesting an involvement of these genes in myoregeneration. Preliminary data show that conditionally inactivated c-Met in adult mouse SCs disrupts injury induced muscle regeneration. Consistent with a role for c-MET in SC migration, c-Met mutant SCs do not accumulate at a defined muscle injury site. These preliminary data indicate that c-MET signaling enables SC migration and potentially other aspects of the SC response to muscle injury.
Aim 1) Because c-MET elicits multiple signaling cascades, the parameters of the c-Met mutant SC phenotype will be defined.
Aim 2) The extent of normal SC migration and the role that c- MET and HGF play in directing SCs to an injury site will be determined.
Aim 3) Branches of c-MET signaling important for SC migration and proliferation will be identified and further tested for ability to enhance SC migration and muscle regeneration. Finally, clonal analysis will be used to assess the functional significance of specific branches of c-MET signaling in SCs, potentially leading to a new model of c-MET induced tumorigenesis. The relative contributions of local SC proliferation versus recruitment of migratory SCs to muscle regeneration have long been debated. Moreover, the molecular signals that guide SC to injury sites has not been resolved. Studying the HGF/c-MET axis in SCs will inform these clinically relevant issues. Identifying c-MET effectors in adult muscle precursors is crucial not only for understanding muscle stem cell biology, but also for understanding general principles of stem cell mediated regeneration, and for developing therapies for RMS that exploit c-MET signaling pathways. As deregulation of c-MET signaling is implicated in myriad tumors, this research may be relevant to multiple cancers.
c-Met, a proto-oncogene required for muscle precursor cell migration during development and cancer progression, is expressed in adult muscle stem cells though its function is currently unknown. The goals of this research include 1) identifying c-MET's role in mouse muscle stem cells during muscle regeneration 2) characterizing c-MET's effect on mouse muscle stem cell migration and 3) determining how c-MET enables the invasive behavior of mouse muscle stem cells during muscle regeneration. Findings from this research will be germane to various cancer studies, including Rhabdomyosarcoma that is derived from muscle precursor cells in which c-MET signaling is commonly deregulated.