Our research
Our lab explores the developmental origins of childhood cancer, focusing on the molecular and cellular mechanisms that drive tumor initiation and progression. To study pediatric cancer, we develop and utilize zebrafish genetic and human cancer cell line models to address the following questions:
How are healthy cells transformed into cancer cells in vivo? How do tumor cells hijack developmental signaling pathways during cell transformation, tumor establishment, and cancer niche formation? Can we identify lineage-specific developmental vulnerabilities of cancer cells? Can we use this knowledge for preventive medicine and to develop new treatment strategies?
Modeling Pediatric Cancer in Zebrafish
We are interested in developing zebrafish genetic models of pediatric cancers as a platform for biologics discovery and preclinical testing of novel therapies. These models include oncofusion-driven solid tumors, such as pediatric brain tumors, myoepithelial carcinoma, and Ewing sarcoma.
Zebrafish genetic model of Ewing sarcoma
Genetic models of Ewing sarcoma in zebrafish: Ewing sarcoma is a malignant small round blue cell tumor of bone and soft tissue that affects children, adolescents, and young adults. The cell of origin and mechanisms driving transformation and tumor progression remain debatable in the field. Due to the high toxicity of the oncogenic fusion EWSR1::FLI1, no genetic mouse model exists for in vivo studies. To address this, during her postdoctoral training in Dr. Amatruda’s lab, Elena Vasileva developed mosaic and neural crest zebrafish models of Ewing sarcoma based on Cre-inducible EWSR1::FLI1 expression, providing a platform for biological discovery and preclinical therapeutic testing (Vasileva et al., eLife, 2022).
Proteoglycans in Ewing sarcoma: Using our inducible mosaic zebrafish model of Ewing sarcoma, we demonstrated that tumor growth depends on heparan sulfate proteoglycan (HSPG)-mediated signaling and is associated with MAPK/ERK pathway activation driven by dysregulated HSPG metabolism. Pharmacologic inhibition of HSPGs with surfen reduced ERK1/2 signaling and suppressed Ewing sarcoma tumorigenicity in vitro and in vivo, highlighting the extracellular matrix as a critical regulator of tumor growth and a promising therapeutic target (Vasileva et al., eLife, 2022).
The cell-of-origin for Ewing sarcoma has been a long-standing mystery. Previous studies have proposed bone marrow mesenchyme and neural crest cells as potential cells of origin for Ewing sarcoma, but these hypotheses had not been tested in vivo due to the developmental toxicity of EWSR1::FLI1. To address this, Elena Vasileva developed a stable zebrafish transgenic model with neural crest-specific expression of human EWSR1::FLI1 (Vasileva et al., Cell Reports, 2025). Using this model, we showed that EWSR1::FLI1 can transform neural crest cells in vivo by reprogramming them toward a mesoderm-like, tumor-prone state through hijacking developmental enhancers and activating mesodermal regulators, including tbxta/TBXT. This work provides the first in vivo evidence supporting a neural crest origin for Ewing sarcoma and reveals how a single oncogenic fusion can profoundly rewire cell fate.
Our research approaches
Lineage-tracing and transgenic fish
We develop and use zebrafish transgenic lines and apply a lineage tracing approach to track cell fate changes over time, allowing us to explore origins of pediatric cancers, follow cell transformation, and study how tumors develop and diversify during progression.
Multiomics
We apply single-cell transcriptomic, snATAC-seq, and CUT&RUN approaches to understand the epigenetic and transcriptional changes driven by oncogenic fusions at the single-cell level during cell reprogramming and tumor initiation. We also use single-cell spatial transcriptomics to better understand tumor architecture and heterogeneity.
High-resolution imaging
Zebrafish are optically transparent, and in our models, tumor cells are labeled with fluorescent reporters, enabling real-time visualization and tracking of pre-cancerous and cancer cells in a living, developing organism using high-resolution microscopy.
Zebrafish as a screening platform
Zebrafish offer a scalable in vivo system for genetic and chemical screening, allowing rapid testing of candidate genes and identification of compounds that impact tumor growth and progression.
By integrating innovative zebrafish models with cutting-edge single-cell transcriptomics, genetic tools, and high-resolution imaging, we aim to define the cellular mechanisms of tumor development in a physiologically relevant developmental context and leverage this system as a platform for validation of new targets and high-throughput drug screening. We also complement our models with human cancer cell lines and molecular biology and biochemistry approaches.
Our research directions
Zebrafish models of pediatric cancer
Our lab develops zebrafish genetic models of pediatric cancer by introducing cancer-associated mutations identified in human tumors into zebrafish. These models allow us to study tumor initiation and progression in an in vivo developmental context.
Cancer cell of origin
Understanding the cancer cell of origin is critical for uncovering lineage-specific vulnerabilities in cancer. We investigate how oncogenic fusions rewire cell identity and disrupt normal developmental trajectories.
Cancer-niche communication
Tumors arise within a dynamic developmental environment where interactions with surrounding cells can strongly influence disease progression. We investigate how proteoglycans regulate tumor–microenvironment interactions and support pediatric cancer growth.
Developmental vulnerabilities
This project aims to uncover developmental pathways co-opted by tumor cells. We will modulate cancer cell differentiation states through targeting developmental regulators to affect tumor growth and metastatic behavior.
