AUTHOR=Allen Tyler A. , Cullen Mark M. , Hawkey Nathan , Mochizuki Hiroyuki , Nguyen Lan , Schechter Elyse , Borst Luke , Yoder Jeffrey A. , Freedman Jennifer A. , Patierno Steven R. , Cheng Ke , Eward William C. , Somarelli Jason A. 

TITLE=A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.641187

DOI=10.3389/fonc.2021.641187

ISSN=2234-943X

ABSTRACT=<p>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 <italic>intravital</italic> 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 &lt; 0.05). Within the extracellular matrix remodeling pathway, we identified versican (<italic>VCAN</italic>) as consistently upregulated and central to the ECM gene regulatory network (p &lt; 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.</p>