Stem cells have the ability to self-renew and differentiate into a variety of tissue types. They also play an important role in tumor relapse andprogression in cancer. The molecular mechanism regulating stem cell function remains poorly understood. Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue malignancy in children with pathologic features of abnormal fetal muscle development. It is thought that the cancer stem cells contribute to treatment resistance and tumor relapse. We have previously identified the self-renewing tumor-initiating cell population in a zebrafish model of ERMS, which shows morphologic and molecular features resembling the human counterpart. We have also shown that the self-renewing ERMS cell is molecularly similar to an activated satellite cell in muscle. In skeletal muscle, satellite cells are a population of muscle progenitorcells that play an essential role in postnatal growth, repair and regeneration. Our central hypothesis is that there are common pathways that regulate stem cell function in muscle regeneration and progression of rhabdomyosarcoma. In this proposed study, we will identify FDA-approved drugs that act as positive and negative regulators of stem cell renewal in muscle regeneration and ERMS. We will then determine the common molecular pathways that alter stem cell function in muscle and characterize the mechanism by which each candidate pathway exerts its effect on muscle self- renewal. Our long-term goal is to better understand mechanisms underlying regulation of muscle stem cell function. The candidate for this career development award is an M.D./Ph.D. physician scientist with board certification in anatomic pathology. The research proposed in this grant application will be conducted under the mentorship of Dr. David Langenau. The candidate is committed to a career as a physician scientist and seeks further scientific training. This mentored clinical scientist development award will facilitate the candidate's transition to eventually become a competitive NIH-funded independent investigator.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Boyce, Amanda T
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University of Washington
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Phelps, Michael; Chen, Eleanor (2016) Zebrafish Rhabdomyosarcoma. Adv Exp Med Biol 916:371-89
Kehrli, Keffy; Phelps, Michael; Lazarchuk, Pavlo et al. (2016) Class I Histone Deacetylase HDAC1 and WRN RECQ Helicase Contribute Additively to Protect Replication Forks upon Hydroxyurea-induced Arrest. J Biol Chem 291:24487-24503
Vleeshouwer-Neumann, Terra; Phelps, Michael; Bammler, Theo K et al. (2015) Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma. PLoS One 10:e0144320
Chen, Eleanor Y; DeRan, Michael T; Ignatius, Myron S et al. (2014) Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:5349-54
Chen, Eleanor Y; Dobrinski, Kimberly P; Brown, Kim H et al. (2013) Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLoS Genet 9:e1003727
Ignatius, Myron S; Chen, Eleanor; Elpek, Natalie M et al. (2012) In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell 21:680-93