Cancer is a complex disease and is ideally studied in a natural environment as it is greatly influenced by cell interactions, but also by mechanical cues from the surrounding tissue.
The zebrafish is a vertebrate model organism gaining increasing attention in cancer research. Offering fantastic live imaging abilities, zebrafish allow us to follow cancer cells within the intact organism and monitor interactions with other cell types at great detail. Furthermore, zebrafish are well suited to carry out preclinical drug screens in vivo. We make use of these advantages and model pediatric cancer in zebrafish to better understand tumor onset and progression.
To model pediatric cancer, we follow two complementary approaches: a genetic modelling and a xenotransplantation strategy (Figure 1). In our models, we are able to observe tumor cell behavior down to the subcellular level by intravital microscopy and we can capture interactions with the tumor microenvironment. Here, we have a particular interest in interactions with innate immune cells to investigate their pro- and anti-tumor roles.
Zebrafish models of pediatric sarcomas
Ewing sarcoma and osteosarcoma are the most frequent bone cancers found in children and young adolescents with dismal outcome, especially for patients with metastasis or after relapse. We are applying zebrafish in innovative ways to tackle open questions like: What is the cell of origin in Ewing sarcoma? What are main drivers of metastasis in Osteosarcoma?
We have successfully established zebrafish xenograft models for Ewing sarcoma and Osteosarcoma (Figure 2). We our now applying these models in drug screens to identify novel therapeutic strategies.
Figure 1: Strategies to model cancer in zebrafish
In vivo drug screening
We have developed a drug screening platform – Zebrafish platform Austria for preclinical drug screening (ZANDR), which is specifically designed to screen small compounds on zebrafish disease models in an automated fashion (see www.zandr-ccri.at). Our recent screen identified compounds and particular compound combinations, which are highly effective against Ewing sarcoma cells in our xenograft setting. We anticipate, that drug screening in zebrafish will provide valuable information to decide, which compounds to advance towards clinical application.
Figure 2: Zebrafish Ewing sarcoma xenograft
We are striving to enhance the available tools and methods for zebrafish research with a current focus on
- bringing new imaging modalities to zebrafish
- generating signaling pathway reporter strains in zebrafish
- automating the small compound screening workflow for zebrafish
- adapting non-neural optogenetic and photopharmaceutical tools for zebrafish and applying them in cancer research
Projects and Funding
- Establishing light-mediated clonal cancer models to investigate tumor initiation
CCRI responsible researcher: Adam Varady (supervisor: Martin Distel)
Grant from the Austrian Academy of Sciences (ÖAW), DOC fellowship, ID – 25931
Duration: 01/08/2021 to 01/02/2024
- Identifying the Ewing Sarcoma cell-of-origin by cross-species enhancer activity analysis
CCRI responsible researcher: Sarah Grissenberger (supervisor: Martin Distel)
Grant from the Austria Academy of Sciences (ÖAW), DOC fellowship, ID – 25607
Duration: 01/03/2020 to 01/09/2022
- Tracking Ewing sarcoma origin by developmental and trans-species genomics (ORIGIN)
CCRI responsible Principal Investigator and Coordinator: Heinrich Kovar
Additional CCRI Principal Investigators: Martin Distel, Florian Halbritter
Alex´s Lemonade Stand Foundation (ALSF), Crazy 8 Initiative Award Program
Duration: 01/03/2021 to 28/02/2025
- Comprehensive cell contact tracing (C3T)
CCRI responsible Principal Investigator: Florian Halbritter
Additional CCRI Principal Investigators: Martin Distel
Grant from the Austrian Science Fund (FWF), TAI-1000 Ideas Program, ID – TAI 454
Duration: 01/09/2021 to 31/12/2022
Andreana, M, Sturtzel, C, Spielvogel, CP, Papp, L, Leitgeb, R, Drexler, W, Distel, M & Unterhuber, A (2021) Toward Quantitative in vivo Label-Free Tracking of Lipid Distribution in a Zebrafish Cancer Model. Front Cell Dev Biol 9, 675636, doi:10.3389/fcell.2021.675636.
Varady, A & Distel, M (2020) Non-neuromodulatory Optogenetic Tools in Zebrafish. Front Cell Dev Biol 8, 418, doi:10.3389/fcell.2020.00418.
Pascoal S, Salzer B, Scheuringer E, Wenninger-Weinzierl A, Sturtzel C, Holter W, Taschner-Mandl S, Lehner M, Distel M (2020) A Preclinical Embryonic Zebrafish Xenograft Model to Investigate CAR T Cells In Vivo. Cancers (Basel). Feb 29;12(3):567. doi: 10.3390/cancers12030567.
Mayr V, Sturtzel C, Stadler M, Grissenberger S, Distel M (2018) Fast Dynamic in vivo Monitoring of Erk Activity at Single Cell Resolution in DREKA Zebrafish. Front Cell Dev Biol. 2018 Sep 25;6:111. doi: 10.3389/fcell.2018.00111.
Kirchberger S, Sturtzel C, Pascoal S, and Distel M (2017) Quo natas, Danio?-Recent Progress in Modeling Cancer in Zebrafish. Front Oncol. 7: p. 186.DOI: 10.3389/fonc.2017.00186.
About Martin Distel
Dr. Martin Distel (PhD) studied Molecular Biotechnology at the Technical University Munich, Germany, and at Lund University, Sweden. He performed his PhD at the Helmholtz Center Munich, Germany, under the supervision of Reinhard Köster, developing genetic gene expression tools to study the development of the cerebellum in zebrafish. He also worked with Daniel Razansky at the Helmholtz Center Munich to bring opto-acoustic imaging to zebrafish. For his postdoctoral work in the field of zebrafish hematopoiesis, he joined the lab of David Traver at the University of California, San Diego.
In 2014 Martin joined CCRI as group leader, where he established a zebrafish lab and a zebrafish facility. Since 2017, he is also head of the Zebrafish platform Austria for preclinical drug screening at CCRI.