YAP Enhances Tumor Cell Dissemination by Promoting
Intravascular Motility and Reentry into Systemic
Metastasis is the cause of the vast majority of cancer-related mortality. However, we do not yet have a complete understanding of the underlying biology. This lack of understanding is especially true for the events at the metastatic site, which include arrest, extravasation, and growth into macro-metastases. These events are rare, transient, and often and occur deep within vital organs.
Zebrafish embryos offer a powerful platform for imaging tumor cells in circulation and during arrest, extravasation, and growth into new metastases. Zebrafish embryos are transparent and develop outside the mother. Furthermore, by 2 days post-fertilization (dpf) the zebrafish embryo has a fully functional circulatory system. This allows tumor cells to be injected into circulation and followed using confocal microscopy in real time and over the course of multiple days.
We have found that the oncogene YAP promotes brain metastasis in the zebrafish embryo. Through intravital imaging, we observed that following injection, control cells become lodged in narrow vessels in the tail. However, cells that over-express YAP, are able to travel through these vessels and continue through circulation. Many of these cells then go on to seed the brain, a common site of metastasis in humans.
Many cancers commonly metastasize to organs that are the next vascular bed in circulation (eg. colon cancer metastasis to the liver). By enabling tumor cells to travel through this first vascular bed, YAP may allow tumor cells to metastasize more efficiently to a wider range of organs (for example some colon cancer patients have lung metastases which may originate from tumor cells that have traveled through the capillaries in the liver). We are currently performing experiments in mice to confirm if our observations in zebrafish represent a novel mechanism by which tumor cells can enhance their dissemination in mammals.
We are currently preparing these results for publication.