Langenau Lab

About the Lab

Most pediatric patients whose sarcoma or leukemia recurs will succumb to their disease. The focus of the Langenau laboratory is to uncover the mechanisms that drive progression and relapse in pediatric tumors with the long-term goal of identifying new drug targets and therapies to treat relapse and refractory disease.

Identifying molecular pathways that drive progression and relapse in pediatric cancer

The Langenau laboratory uses zebrafish genetic models, human cell lines, patient derived xenografts, and patient samples to uncover progression and relapse mechanisms in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and rhabdomyosarcoma (RMS) muscle cancer. Our work has detailed the remarkable conservation of molecular mechanisms in zebrafish and human cancer and discovered novel biology and new therapies for these diseases. For example, we identified combination Olaparib and temozolomide therapy for the treatment of RMS that is in clinical trial evaluation for RMS patients at Mass General and Dana-Farber Cancer Institute in Boston (NCT01858168, Yan et al., Cell 2019).

Uncovering progression-associated driver mutations in T-cell acute lymphoblastic leukemia

-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 fiveyear 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 mechanisms that cause leukemia cells to re-emerge at relapse. Utilizing a novel zebrafish model of relapse T-ALL, large-scale trangenesis platforms, high-throughput cell transplantation, and unbiased bioinformatic approaches, we have uncovered new oncogenic drivers associated with aggression, therapy resistance and relapse. A large subset of these genes exerts important roles in regulating human T-ALL proliferation, apoptosis and response to therapy. Discovering new relapse-driving oncogenic pathways will likely identify drug targets for the treatment of T-ALL.

Cancer stem cell pathways in pediatric muscle cancer

Rhabdomyosarcoma is a common soft-tissue sarcoma of childhood and phenotypically recapitulates fetal muscle development arrested at early stages of differentiation. Our laboratory has developed transgenic zebrafish models of RMS that mimic the molecular underpinnings of human disease to discover functionally-distinct cell subpopulations, including cancer stems that drive continued tumor growth at relapse. Remarkably these same cell states are found in human disease and drive therapy resistance (Wei et al, Nature Cancer 2022). Our group has also uncovered important roles for WNT, MYOD transcription factors, the VANGL2/non-canonical WNT pathway, NOTCH, and P53 loss in driving continued RMS growth.

Zebrafish avatars of human cancer

The Langenau Lab has generated a number of immunocompromised zebrafish strains that efficiently engraft human tumors. These models are amenable to real-time imaging of cancer hallmarks at single cell resolution and have been used in preclinical modeling experiments to identify drug combinations and new immunotherapy approaches for the treatment of human rhabdomyosarcoma and other cancers. This work has led to the first clinical trial for pediatric cancer originating from findings made in the zebrafish.

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

Danielli SG, Wei Y, Dyer MA, Stewart E, Sheppard H, Wachtel M, Schäfer BW, Patel AG, Langenau DM. Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma. Nat Commun. 2024;15(1):6307

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.