David M. Langenau, PhD
Harvard Medical School
Our research focuses on using the zebrafish to better understand human cancer and to develop novel insights into how it is that tumors can be remade following conventional chemotherapeutic intervention. Uncovering the downstream molecular pathways that lead to relapse will be integral to identifying novel drugs for the treatment of cancer.
I. Identifying the genetic programs underlying self-renewal of rhabdomyosarcoma cancer stem cells
We have shown that expression of activated k-RAS in early muscle cells is sufficient to induce embryonal rhabdomyosarcoma (ERMS) ˆ the most prevalent pediatric subtype of disease. Zebrafish tumors are morphologically similar to human ERMS and express the clinical diagnostic markers of this malignancy. Using fluorescence activated cell sorting and cell transplantation, we have identified the self-renewing cancer stem cell in ERMS, a cell that is most similar to an activated muscle satellite cell. Moreover, we have developed fluorescent transgenic zebrafish that develop ERMS and can visualize malignant cell sub-types in real-time, facilitating assessment of the functional consequences of tumor cell heterogeneity. Together with these imaging studies, we are interrogating the genetic pathways that modulate tumor-propagating cell number, growth, and relapse in ERMS.
II. Uncovering novel driver mutations in T-cell acute lymphoblastic leukemia
T-cell acute lymphoblastic leukemia (T-ALL) is a devastating disease of childhood and is associated with transformation of thymic precursor cells. Using a transgenic zebrafish model of T-ALL, large-scale transplantation experiments have been used to functionally assess relapse and tumor-propagating potential. Our work has shown that T-ALLs can evolve increased percentages of tumor-propagating cells as leukemias continue to grow, suggesting that continued clonal evolution may drive increased malignant phenotypes observed in relapse disease. We are currently assessing which genetic pathways drive increased leukemia-propagating potential during clonal evolution and assessing human relapse associated genes for effects in altering leukemia growth in the zebrafish T-ALL model.