The role of cMET in satellite cells during muscle regeneration

Summary

Principal Investigator: MICAH TAUBE WEBSTER
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-08-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc c-MET regulates myoblast motility and myocyte fusion during adult skeletal muscle regeneration
    Micah T Webster
    Department of Embryology, The Carnegie Institution for Science, Baltimore, Maryland, United States of America
    PLoS ONE 8:e81757. 2013

Research Grants

  1. Molecular Modeling of Pediatric Skeletal Muscle Tumors
    Corinne Mary Linardic; Fiscal Year: 2013
  2. Regulation of Muscle Stem Cell Fate
    Helen M Blau; Fiscal Year: 2013
  3. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
  4. Parkinson's Disease and Dementia
    John Q Trojanowski; Fiscal Year: 2013
  5. Molecular mechanisms of muscle stem cells transitioning intoquiescence
    Christoph Lepper; Fiscal Year: 2013
  6. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
  7. Thyroid Hormone Receptor Isoforms in Skeletal Muscle
    Anna Milanesi; Fiscal Year: 2013
  8. TAK1/TRAF6 Signaling in Skeletal Muscle
    Ashok Kumar; Fiscal Year: 2013
  9. PHYSIOLOGY OF THYROID HORMONE-DEPENDENT GENE EXPRESSION
    PHILIP REED LARSEN; Fiscal Year: 2013
  10. Molecular Mechanisms of Age-related Impairment of Muscle Regeneration
    Thomas A Rando; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc c-MET regulates myoblast motility and myocyte fusion during adult skeletal muscle regeneration
    Micah T Webster
    Department of Embryology, The Carnegie Institution for Science, Baltimore, Maryland, United States of America
    PLoS ONE 8:e81757. 2013
    ..Surprisingly, c-MET was also required for efficient myocyte fusion, implicating c-MET in dual functions of regulating myoblast migration and myocyte fusion. ..

Research Grants30

  1. Molecular Modeling of Pediatric Skeletal Muscle Tumors
    Corinne Mary Linardic; Fiscal Year: 2013
    ..In addition, this genetically defined model will serve as a template for the systematic investigation of other human sarcomas. ..
  2. Regulation of Muscle Stem Cell Fate
    Helen M Blau; Fiscal Year: 2013
    ..A means for growing muscle stem cells in tissue culture without loss of stem cell properties is imperative and is the ultimate aim of this research. ..
  3. UAB / UMN SPORE in Pancreatic Cancer
    Donald J Buchsbaum; Fiscal Year: 2013
    ..The application has strong institutional support from UAB and UMN, excellent pancreatic cancer populations and concurrence with federal guidelines. ..
  4. Parkinson's Disease and Dementia
    John Q Trojanowski; Fiscal Year: 2013
    ..M.-Y. Lee;Project IV: "Immune Therapy To Block PD Transmission In Mice": PL - J.Q. Trojanowski;Co-I - V.M.-Y. Lee and Kelvin Luk. ..
  5. Molecular mechanisms of muscle stem cells transitioning intoquiescence
    Christoph Lepper; Fiscal Year: 2013
    ..I will develop a novel assay for rapid screening of these genes'functions by combining gene knock-down and intramuscular transplantation of muscle stem cells. ..
  6. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  7. Thyroid Hormone Receptor Isoforms in Skeletal Muscle
    Anna Milanesi; Fiscal Year: 2013
    ..This will then allow the applicant to become an independently-funded physician-scientist in the field of endocrinology bridging stem cell research. ..
  8. TAK1/TRAF6 Signaling in Skeletal Muscle
    Ashok Kumar; Fiscal Year: 2013
    ..Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders. ..
  9. PHYSIOLOGY OF THYROID HORMONE-DEPENDENT GENE EXPRESSION
    PHILIP REED LARSEN; Fiscal Year: 2013
    ..We will also determine whether therapeutic manipulations of deiodinase activities could be used to enhance the treatment of conditions such as traumatic or degenerative muscle injury or the sarcopenia of the elderly. ..
  10. Molecular Mechanisms of Age-related Impairment of Muscle Regeneration
    Thomas A Rando; Fiscal Year: 2013
    ..Together, these studies offer great hope to the development of therapies that will promote healing of injured tissues in the aging veteran population. ..
  11. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  12. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  13. Regulation and function of Six1 in zebrafish muscle development and in rhabdomyos
    JENEAN O'BRIEN; Fiscal Year: 2013
    ....
  14. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  15. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  16. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
    ....
  17. Investigation of Sulf regulation on the noncanonical Wnt signaling pathway
    Thanh Huu Tran; Fiscal Year: 2013
    ..We will also utilize lentivirus expressing the dominant negative Sulf2 to acutely inactivate Sulfs. ..
  18. Neural Mechanisms of Itch
    ROBERT H LA MOTTE; Fiscal Year: 2013
    ..abstract_text> ..
  19. Soluble Motogens and Chemoattractants from Damaged Muscle
    DAWN D CORNELISON; Fiscal Year: 2013
    ....