David M. Langenau

David M. Langenau

Associate Professor of Pathology
David M. Langenau
The Langenau laboratory research focus is to uncover relapse mechanisms that enhance growth and tumor propagating cell frequency in pediatric cancer. Utilizing zebrafish models of T-cell acute lymphoblastic leukemia (T-ALL) and embryonal rhabdomysoarcoma (ERMS), we have undertaken chemical and genetic approaches to identify novel modulators of growth and relapse. I. Uncovering relapse-associated driver mutations in T-cell acute lymphoblastic leukemiaT-ALL is an aggressive malignancy of thymocytes that affects thousands of children and adults in the United States each year. Recent advancements in conventional chemotherapies have improved the five-year survival rate of patients with T-ALL. However, patients with relapse disease are largely unresponsive to additional therapy and have a very poor prognosis. Ultimately, 70% of children and 92% of adults will die of relapse T-ALL, underscoring the clinical imperative for identifying the molecular mechanisms that cause leukemia cells to re-emerge at relapse. Our hypothesis is that relapse clones harbor novel genomic changes that enhance survival, regrowth, and therapy resistance with clonally heterogeneity ultimately driving relapse. Identifying novel relapse-driving oncogenic pathways will likely identify new drug targets for the development of small molecule inhibitors as therapeutics for this disease. Utilizing a novel zebrafish model of relapse T-ALL and unbiased bioinformatic approaches, we have recently uncovered new oncogenic drivers associated with aggression, growth and increased propensity for relapse. A subset of these genes is being assessed for a role in regulating T-ALL proliferation, apoptosis and response to therapy in human disease. II. Visualizing and killing cancer stem cells in embryonal rhabdomyosarcomaERMS is a common soft-tissue sarcoma of childhood and phenotypically recapitulates fetal muscle development arrested at early stages of differentiation. Microarray and cross-species comparisons of zebrafish, mouse and human ERMS uncovered the finding that the RAS pathway is activated in a majority of ERMS. Building on this finding, our laboratory has developed a transgenic zebrafish model of kRASG12D-induced ERMS that mimics the molecular underpinnings of human ERMS. Using fluorescent transgenic zebrafish that label ERMS cell subpopulations based on myogenic factor expression, we have identified functionally distinct classes of tumor cells contained within the ERMS mass. Specifically, the myf5-GFP+ self-renewing cancer stem cell drives continued tumor growth and is molecularly similar to a non-transformed, activated muscle satellite cell. Paradoxically, it is the differentiated, non-proliferative myogenin+ ERMS cells that are highly migratory and the first cells to colonize newly formed tumors rather than the myf5+ ERMS-propagating cells. Our data suggest that non-tumor-propagating cells likely have important supportive roles in cancer progression and facilitate metastasis. Building on the dynamic live cell imaging approaches available in the zebrafish ERMS model, our laboratory has undertaken chemical genetic approaches to identify drugs that kill relapse-associated, self-renewing myf5-GFP+ ERMS cells. A subset of drugs is currently being assessed for regulating growth of human ERMS cells.

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Massachusetts General Hospital
149 13th Street, 6th Floor, Room 6012
Charlestown MA 02129
p: 617-643-6508

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