PUBLICATION
A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation
- Authors
- Allen, T.A., Cullen, M.M., Hawkey, N., Mochizuki, H., Nguyen, L., Schechter, E., Borst, L., Yoder, J.A., Freedman, J.A., Patierno, S.R., Cheng, K., Eward, W.C., Somarelli, J.A.
- ID
- ZDB-PUB-211012-8
- Date
- 2021
- Source
- Frontiers in oncology 11: 641187 (Journal)
- Registered Authors
- Yoder, Jeffrey A.
- Keywords
- angiopellosis, cancer exodus hypothesis, circulating tumor cell cluster, metastasis, osteosarcoma, tumor cell extravasation
- MeSH Terms
- none
- PubMed
- 34631514 Full text @ Front Oncol
Citation
Allen, T.A., Cullen, M.M., Hawkey, N., Mochizuki, H., Nguyen, L., Schechter, E., Borst, L., Yoder, J.A., Freedman, J.A., Patierno, S.R., Cheng, K., Eward, W.C., Somarelli, J.A. (2021) A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation. Frontiers in oncology. 11:641187.
Abstract
Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under intravital imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican (VCAN) as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping