David M. Langenau, PhD
Professor of Pathology, Harvard Medical School
Associate Chief of Pathology (Research), Massachusetts General Hospital
Director, Molecular Pathology Unit, Massachusetts General Hospital
Member, MGH Cancer Center and Center for Regenerative Medicine
149 13th Street, #6012
Molecular Pathology Unit
Charlestown, MA 02129
Explore This Lab
About the Lab
The Langenau laboratory research focus is to uncover relapse mechanisms in pediatric cancer. Utilizing zebrafish models of embryonal rhabdomysoarcoma (ERMS) and T-cell acute lymphoblastic leukemia (T-ALL), we have undertaken chemical and genetic approaches to identify novel modulators of progression, therapy-resistance, and relapse.
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 that the RAS pathway is activated in a majority of ERMS. Building on this discovery, our laboratory has developed a transgenic zebrafish model of RAS-induced ERMS that mimics the molecular underpinnings of human ERMS. We used fluorescent transgenic zebrafish to label functionally distinct tumor cells. Specifically, the myf5-GFP+ self-renewing cancer stem cells drive continued tumor growth at relapse and are molecularly similar to non-transformed, activated muscle satellite cells.
Building on the dynamic live cell imaging approaches available in the zebrafish ERMS model, our laboratory has uncovered a number of molecular pathways that drive continued tumor growth and progression by regulating cancer stem cell function. Finally, using chemical genetic approaches, we have identified drugs that kill relapse-associated, self-renewing ERMS cells. We are currently assessing the genetic pathways uncovered by our work and a subset of drugs for their ability to regulate growth of patient-derived xenografts.
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 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 exerts an important role 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.
Yan C, Brunson DC, Tang Q, Do D, Iftimia NA, Moore JC, Hayes MN, Welker AM, Garcia EG, Dubash TD, Hong X, Drapkin BJ, Myers DT, Phat S, Volorio A, Marvin DL, Ligorio M, Dershowitz L, McCarthy KM, Karabacak MN, Fletcher JA, Sgroi DC, Iafrate JA, Maheswaran S, Dyson NJ, Haber DA, Rawls JF, Langenau DM. Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish. Cell. 2019; 177(7):1903-1914.
Hayes MN, McCarthy K, Jin A, Oliveira ML, Iyer S, Garcia SP, Sindiri S, Gryder B, Motala Z, Nielsen GP, Borg JP, van de Rijn M, Malkin D, Khan J, Ignatius MS, Langenau DM. Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma. Cell Stem Cell. 2018; 22(3):414-427.
Lobbardi R, Pinder J, Martinez-Pastor B, Theodorou M, Blackburn JS, Abraham BJ, Namiki Y, Mansour M, Abdelfattah NS, Molodtsov A, Alexe G, Toiber D, de Waard M, Jain E, Boukhali M, Lion M, Bhere D, Shah K, Gutierrez A, Stegmaier K, Silverman LB, Sadreyev RI, Asara
JM, Oettinger MA, Haas W, Look AT, Young RA, Mostoslavsky R, Dellaire G, Langenau DM. TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia. Cancer Discov. 2017; 7(11):1336-1353.
Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE, Martinez SA, Chen EY, Lee C, Langenau DM. Clonal evolution enhances leukemia- propagating cell frequency in T-cell acute lymphoblastic leukemia through AKT/mTORC1 pathway activation. Cancer Cell. 2014; 25(3):366-78.