BIOGRAPHY AND RESEARCH INTERESTS
ZFIN ID: ZDB-PERS-150915-2
My research interests are in developing genetic and translational zebrafish models of sarcoma. Specifically, I am developing zebrafish models of alveolar rhabdomyosarcoma (ARMS), an aggressive cancer of the muscle occurring in young children and adolescents. Despite many years of attempts to intensify and improve chemotherapy regimens, survival of patients with ARMS remains poor, especially for those who have advanced disease at the time of diagnosis. An important insight into the cause of ARMS came from the discovery that these tumors harbor a chromosomal translocation between the PAX3 or PAX7 genes and the FOXO1 gene. PAX3-FOXO1 and PAX7-FOXO1 fusions are thought to act as aberrant transcription factors, regulating hundreds or even thousands of genes to transform a normal muscle precursor cell into an ARMS tumor. My research focuses on the PAX3-FOXO1 fusion, which causes the most severe form of ARMS, with the goal of understanding how the PAX3-FOXO1 oncogene initiates and drives ARMS tumorigenesis. I am developing PAX3-FOXO1 driven ARMS models to delineate the cell(s)-of-origin and the tumorigenic capacity of different lineages, and define signaling pathways that are aberrantly regulated by PAX3-FOXO1, which may present opportunities for targeted therapies. In addition, this ARMS zebrafish model will be used to characterize how specific mutations or genes may cooperate with PAX3-FOXO1 in driving malignant transformation. By performing a cross-species comparative oncology analysis of zebrafish and human ARMS, this approach aims to pinpoint the most important drivers of disease pathology. Finally, given the strengths of the zebrafish system for chemical biology, this zebrafish ARMS model will be utilized to identify drugs that inhibit PAX3-FOXO1 function either directly or through downstream targets.
Kendall, G.C., Watson, S., Xu, L., LaVigne, C.A., Murchison, W., Rakheja, D., Skapek, S.X., Tirode, F., Delattre, O., Amatruda, J.F. (2018) PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.. eLIFE. 7
G. C. Kendall, E. I. Mokhonova, M. Moran, N. E. Sejbuk, D. W. Wang, O. Silva, R. T. Wang, L. Martinez, Q. L. Lu, R. Damoiseaux, M. J. Spencer, S. F. Nelson, M. C. Miceli, Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy. Sci. Transl. Med. 4, 164ra160 (12 December 2012).