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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.

Read more about the Langenau Lab from the Krantz Family Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.

Selected Publications

PubMed Bibliography

Wei Y, Qin Q, Yan C, Hayes MN, Garcia SP, Xi H, Do D, Jin AH, Eng TC, McCarthy KM, Adhikari A, Onozato ML, Spentzos D, Neilsen GP, Iafrate AJ, Wexler LH, Pyle AD, Suvà ML, Dela Cruz F, Pinello L, Langenau DM. Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma. Nat Cancer. 2022;3(8):961-975.

Laukkanen S, Bacquelaine Veloso A, Yan C, Oksa L, Alpert EJ, Do D, Hyvärinen N, McCarthy K, Adhikari A, Yang Q, Iyer S, Garcia SP, Pello A, Ruokoranta T, Moisio S, Adhikari S, Yoder JA, Gallagher KM, Whelton L, Allen JR, Jin AH, Loontiens S, Heinäniemi M, Kelliher MA, Heckman CA, Lohi O, Langenau DM. Combination therapies to inhibit LCK tyrosine kinase and mTOR signaling in T-cell Acute Lymphoblastic Leukemia. Blood. 2022, 140(17):1891-1906.

Yan C, Yang Q, Zhang S, Millar DG, Alpert EJ, Do D, Veloso A, Brunson DC, Drapkin BJ, Stanzione M, Scarfo I, Moore J, Iyer S, Qin Q, Wei Y, McCarthy KM, Rawls JF, Dyson NJ, Cobbold M, Maus M, Langenau DM. Single cell imaging of T cell immunotherapy responses in vivo. J Exp Med. 2021; 218(10):e20210314.

Patton EE, Zon LI, Langenau DM. Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials. Nat Rev Drug Discov. 2021;20(8):611-628.

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.