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Research at Mass General
David M. Langenau, PhD
Associate Professor of Pathology, Harvard Medical SchoolDirector, Molecular Pathology Unit, Massachusetts General HospitalMember, MGH Cancer Center and Center for Regenerative Medicine
Massachusetts General HospitalMolecular Pathology Unit149 13th Street, 6th FloorCharlestown, MA 02129Phone: email@example.com
The Langenau laboratory research focus is to uncover relapse mechanisms in pediatric cancer. Utilizing zebrafish models of T-cell acute lymphoblastic leukemia (T-ALL) and embryonal rhabdomyosarcoma (ERMS), we have undertaken chemical and genetic approaches to identify novel modulators of progression, therapy-resistance, and relapse.
Most pediatric patients whose sarcoma or leukemia recurs will succumb to their disease. The focus of the Langenau lab is to uncover the mechanisms that drive progression and relapse in pediatric tumors with the long-term goal of identifying new therapeutic drug targets to treat relapse and refractory disease. One approach we have used is to add drugs to the water of novel zebrafish models of pediatric sarcoma and leukemia that mimic human malignancy. We then imaged tumor growth in the zebrafish and utilize detailed imaging studies to visualize tumor cells in live animals to assess how cellular heterogeneity drives continued tumor growth. Capitalizing on insights gained from our zebrafish models of cancer, we are now extending our findings to human T-cell acute lymphoblastic leukemia and rhabdomyosarcoma.
The First Subspecialized Pathology Service Uncovering progression=associated driver mutations in T-cell acute lymphoblastic leukemia
T-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. Utilizing a novel zebrafish model of relapse T-ALL, large-scale trangenesis platforms, and unbiased bioinformatic approaches, we have uncovered new oncogenic drivers associated with aggression, therapy resistance and relapse. A large subset of these genes exert important roles in regulating human T-ALL proliferation, apoptosis and response to therapy. Discovering novel relapse-driving oncogenic pathways will likely identify new drug targets for the treatment of T-ALL.
Visualizing and killing cancer stem cells in embryonal rhabdomyosarcoma
ERMS 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 discovery, our laboratory has developed a transgenic zebrafish model of kRASG12D-induced ERMS that mimics the molecular underpinnings of human ERMS. We used fluorescent transgenic zebrafish that label ERMS cell subpopulations based on myogenic factor expression to identify functionally distinct classes of tumor cells contained within the ERMS mass. Specifically, the myf5-GFP+ self-renewing cancer stem cell drives continued tumor growth at relapse and is molecularly similar to a non-transformed, activated muscle satellite cell. 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. We are currently assessing a subset of drugs for their ability to regulate growth of human ERMS cells and mouse xenografts.
Read more about the Langenau Lab from the Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.
Elaine Garcia* Madeline Hayes, PhD David M. Langenau, PhD Mariana Lobato de Oliveira*Karin McCarthy John Moore, PhD Ashwin Ramakrishnan Qin Tang* Ines Tenente* Alessandra Welker, PhD
Complete Bibliography of David M. Langenau via PubMed
Single-cell transcriptional analysis of normal, aberrant, and malignant hematopoiesis in zebrafish. Moore FE, Garcia EG, Lobbardi R, Jain E, Tang Q, Moore JC, Cortes M, Molodtsov A, Kasheta M, Luo CC, Garcia AJ, Mylvaganam R, Yoder JA, Blackburn JS, Sadreyev RI, Ceol CJ, North TE, Langenau DM. J Exp Med. 2016 May 30;213(6):979-92.
Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish. Qin Tang, John C. Moore, Myron S. Ignatius, Inês M. Tenente, Madeline N. Hayes, Elaine G. Garcia, Nora Torres Yordán, Caitlin Bourque, Shuning He, Jessica S. Blackburn, A. Thomas Look, Yariv Houvras, David M. Langenau. Nat Commun. 2016; 7: 10358.
Optimized cell transplantation using adult rag2 mutant zebrafish. Qin Tang, Nouran S. Abdelfattah, Jessica S. Blackburn, John C. Moore, Sarah A. Martinez, Finola E. Moore, Riadh Lobbardi, Inês M. Tenente, Myron S. Ignatius, Jason N. Berman, Robert S. Liwski, Yariv Houvras, David M. Langenau. Nat Methods. 2014 Aug; 11(8): 821–824.
Clonal evolution enhances leukemia propagating cell frequency in T-cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation Jessica S. Blackburn, Sali Liu, Jayme L. Wilder, Kimberly P. Dobrinski, Riadh Lobbardi, Finola E. Moore, Sarah A. Martinez, Eleanor Y. Chen, Charles Lee, David M. Langenau. Cancer Cell. 2014 Mar 17; 25(3): 366–378.
Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Eleanor Y. Chen, Michael T. DeRan, Myron S. Ignatius, Kathryn Brooke Grandinetti, Ryan Clagg, Karin M. McCarthy, Riadh M. Lobbardi, Jillian Brockmann, Charles Keller, Xu Wu, David M. Langenau. Proc Natl Acad Sci U S A. 2014 Apr 8; 111(14): 5349–5354.
In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Myron S. Ignatius, Eleanor Chen, Natalie M. Elpek, Adam Fuller, Inês M. Tenente, Ryan Clagg, Sali Liu, Jessica S. Blackburn, Corinne M. Linardic, Andrew Rosenberg, Petur G. Nielsen, Thorsten R. Mempel, David M. Langenau. Cancer Cell. 2012 May 25; 21(5): 680–693.
Massachusetts General Hospital
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