David Langenau, PhD
Assistant Professor, Department of Pathology, Harvard Medical School
Assistant Molecular Pathologist, Molecular Pathology, Massachusetts General Hospital
DF/HCC Program AffiliationLeukemia
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Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation and is strongly associated with RAS pathway activation. Treatment of this disease is very aggressive, and it is likely that improvements in clinical outcome will center on the elimination of cancer stem cells contained within the tumor mass. We have previously created a transgenic zebrafish model of RAS-induced ERMS, demonstrated that zebrafish and human ERMS are morphologically and molecularly similar based on cross-species microarray comparisons, and identified a sub-population of tumor cells that engrafts efficiently into irradiated recipients. When coupled with gene expression studies of this cell population, our data suggest that the cancer stem cell in ERMS is most similar to an activated satellite cell. Building on these observations, we have created transgenic zebrafish that express GFP, mCherry, Amcyan, and zsYellow in developing muscle (myf5-GFP, myogenin-mCherry, mylz2-Amcyan, and creatine kinase-zsYellow) and are using these transgenic reporter lines to further refine the cancer stem cell population. Specifically, cell transplantation of FACS sorted cell populations and live animal confocal imaging are being used to identify and visualize tumor stem cells in vivo. The long-term goal of this work is to define the kinetics of self-renewal in vivo and then identify modifying gene pathways in proliferation and self-renewal. In addition to imaging stem cells in established ERMS, confocal imaging has also been utilized to define tumor progression. Five distinct stages of tumor formation have been identified based on confined tumor growth in myotome segments (stages 1-2), recruitment of vasculature (defined by fli1-GFP, earliest remodeling seen by stage 3), individual cell movement across the horizontal myosepta and myotome boundaries (stage 4), and finally breakdown of muscle architecture and development of tumor masses (stage 5). Additionally, we have used imaging methods to visualize tumor growth during therapeutic intervention and have identified chemical suppressors of tumor formation in zebrafish RMS, including rapamycin and MAP kinase inhibitors. Our work provides new platforms for imaging important processes in cancer progression including stem cell self-renewal, neovascularization, cell migration, and metastatsis.
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