Photo of David Langenau,  PhD

David Langenau, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 643-6508


dlangenau@partners.org

David Langenau, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Associate Professor, Pathology, Harvard Medical School
  • Assistant Molecular Pathologist, Molecular Pathology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

The Langenau laboratory research focus is to uncover relapse mechanisms that alter growth, therapy resistance, 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. One research project focused on 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. The second major research focus of our group is to visualize and kill 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 nontransformed, 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.

 

Publications

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  • Tang Q, Abdelfattah NS, Blackburn JS, Moore JC, Martinez SA, Moore FE, Lobbardi R, Tenente IM, Ignatius MS, Berman JN, Liwski RS, Houvras Y, Langenau DM. Optimized cell transplantation using adult rag2 mutant zebrafish. Nat Methods 2014. PubMed
  • Abraham J, Nuñez-Álvarez Y, Hettmer S, Carrió E, Chen HI, Nishijo K, Huang ET, Prajapati SI, Walker RL, Davis S, Rebeles J, Wiebush H, McCleish AT, Hampton ST, Bjornson CR, Brack AS, Wagers AJ, Rando TA, Capecchi MR, Marini FC, Ehler BR, Zarzabal LA, Goros MW, Michalek JE, Meltzer PS, Langenau DM, LeGallo RD, Mansoor A, Chen Y, Suelves M, Rubin BP, Keller C. Lineage of origin in rhabdomyosarcoma informs pharmacological response. Genes Dev 2014; 28:1578-91. PubMed
  • Blackburn JS, Langenau DM. Zebrafish as a model to assess cancer heterogeneity, progression and relapse. Dis Model Mech 2014; 7:755-762. PubMed
  • Chen EY, Deran MT, Ignatius MS, Grandinetti KB, Clagg R, McCarthy KM, Lobbardi RM, Brockmann J, Keller C, Wu X, Langenau DM. Glycogen synthase kinase 3 inhibitors induce the canonical WNT/硫-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A 2014; 111:5349-54. PubMed
  • Gutierrez A, Feng H, Stevenson K, Neuberg DS, Calzada O, Zhou Y, Langenau DM, Look AT. Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish. British Journal of Haematology 2014. PubMed
  • 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; 25:366-78. PubMed
  • Langenau DM. Pten regulates zebrafish hematopoiesis. Blood 2014; 123:149-50. PubMed
  • Tenente IM, Tang Q, Moore JC, Langenau DM. Normal and malignant muscle cell transplantation into immune compromised adult zebrafish. 2015. PubMed
  • Chen EY, Dobrinski KP, Brown KH, Clagg R, Edelman E, Ignatius MS, Chen JY, Brockmann J, Nielsen GP, Ramaswamy S, Keller C, Lee C, Langenau DM. Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLoS Genet. 2013; 9:e1003727. PubMed
  • Storer NY, White RM, Uong A, Price E, Nielsen GP, Langenau DM, Zon LI. Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis. Development 2013; 140:3040-50. PubMed
  • Sokolowski E, Turina CB, Kikuchi K, Langenau DM, Keller C. Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma. Oncogene 2013. PubMed
  • Le X, Pugach EK, Hettmer S, Storer NY, Liu J, Wills AA, Dibiase A, Chen EY, Ignatius MS, Poss KD, Wagers AJ, Langenau DM, Zon LI. A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development. Development 2013. PubMed
  • Ignatius MS, Chen E, Elpek NM, Fuller AZ, Tenente IM, Clagg R, Liu S, Blackburn JS, Linardic CM, Rosenberg AE, Nielsen PG, Mempel TR, Langenau DM. In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell 2012; 21:680-93. PubMed
  • Moore FE, Reyon D, Sander JD, Martinez SA, Blackburn JS, Khayter C, Ramirez CL, Joung JK, Langenau DM. Improved somatic mutagenesis in zebrafish using transcription activator-like effector nucleases (TALENs). PLoS ONE 2012; 7:e37877. PubMed
  • Moore FE, Langenau DM. Through the looking glass: visualizing leukemia growth, migration, and engraftment using fluorescent transgenic zebrafish. Adv Hematol 2012; 2012:478164. PubMed
  • Blackburn JS, Liu S, Raimondi AR, Ignatius MS, Salthouse CD, Langenau DM. High-throughput imaging of adult fluorescent zebrafish with an LED fluorescence macroscope. Nat Protoc 2011; 6:229-41. PubMed
  • Sander JD, Dahlborg EJ, Goodwin MJ, Cade L, Zhang F, Cifuentes D, Curtin SJ, Blackburn JS, Thibodeau-Beganny S, Qi Y, Pierick CJ, Hoffman E, Maeder ML, Khayter C, Reyon D, Dobbs D, Langenau DM, Stupar RM, Giraldez AJ, Voytas DF, Peterson RT, Yeh JR, Joung JK. Selection-free zinc-finger-nuclease engineering by context-dependent assembly (CoDA). Nat Methods 2010; 8:67-9. PubMed
  • Feng H, Stachura DL, White RM, Gutierrez A, Zhang L, Sanda T, Jette CA, Testa JR, Neuberg DS, Langenau DM, Kutok JL, Zon LI, Traver D, Fleming MD, Kanki JP, Look AT. T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell 2010; 18:353-66. PubMed
  • Smith AC, Raimondi AR, Salthouse CD, Ignatius MS, Blackburn JS, Mizgirev IV, Storer NY, de Jong JL, Chen AT, Zhou Y, Revskoy S, Zon LI, Langenau DM. High-throughput cell transplantation establishes that tumor-initiating cells are abundant in zebrafish T-cell acute lymphoblastic leukemia. Blood 2010; 115:3296-303. PubMed
  • Blackburn JS, Langenau DM. aMAZe-ing tools for mosaic analysis in zebrafish. Nat Methods 2010; 7:188-90. PubMed
  • Ignatius MS, Langenau DM. Zebrafish as a model for cancer self-renewal. Zebrafish 2010; 6:377-87. PubMed
  • Langenau DM, Keefe MD, Storer NY, Jette CA, Smith AC, Ceol CJ, Bourque C, Look AT, Zon LI. Co-injection strategies to modify radiation sensitivity and tumor initiation in transgenic Zebrafish. Oncogene 2008; 27:4242-8. PubMed
  • Langenau DM, Keefe MD, Storer NY, Guyon JR, Kutok JL, Le X, Goessling W, Neuberg DS, Kunkel LM, Zon LI. Effects of RAS on the genesis of embryonal rhabdomyosarcoma. Genes Dev 2007; 21:1382-1395. PubMed
  • Le X, Langenau DM, Keefe MD, Kutok JL, Neuberg DS, Zon LI. Heat shock-inducible Cre/Lox approaches to induce diverse types of tumors and hyperplasia in transgenic zebrafish. Proc Natl Acad Sci U S A 2007; 104:9410-5. PubMed
  • Langenau DM, Feng H, Berghmans S, Kanki JP, Kutok JL, Look AT. Cre/lox-regulated transgenic zebrafish model with conditional myc-induced T cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2005; 102:6068-73. PubMed
  • Langenau DM,Zon LI. The zebrafish: a new model of T-cell and thymic development. Nat Rev Immunol 2005; 5:307-17. PubMed
  • Langenau DM, Ferrando AA, Traver D, Kutok JL, Hezel JP, Kanki JP, Zon LI, Look AT, Trede NS. In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish. Proc Natl Acad Sci U S A 2004; 101:7369-74. PubMed
  • Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC, Kanki JP, Lin S, Prochownik E, Trede NS, Zon LI, Look AT. Myc-induced T cell leukemia in transgenic zebrafish. Science 2003; 299:887-90. PubMed
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