YAP Enhances Tumor Cell Dissemination by Promoting Intravascular Motility and Reentry into Systemic Circulation
Name
nihms-1608504.pdf
Description
Accepted version
Size
3.12 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Benjamin, David C
Kang, Joon Ho
Hamza, Bashar
King, Emily M
Lamar, John M
Manalis, Scott R
Hynes, Richard O
Date Issued
2020
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
The oncogene YAP has been shown previously to promote tumor growth and metastasis. However, how YAP influences the behavior of tumor cells traveling within the circulatory system has not been as well explored. Given that rate-limiting steps of metastasis are known to occur while tumor cells enter, travel through, or exit circulation, we sought to study how YAP influences tumor cell behavior within the circulatory system. Intravital imaging in live zebrafish embryos revealed that YAP influenced the distribution of tumor cells within the animal following intravenous injection. Control cells became lodged in the first capillary bed encountered in the tail, whereas cells overexpressing constitutively active YAP were able to travel through this capillary plexus, reenter systemic circulation, and seed in the brain. YAP controlled transit through these capillaries by promoting active migration within the vasculature. These results were corroborated in a mouse model following intravenous injection, where active YAP increased the number of circulating tumor cells over time. Our results suggest a possible mechanism whereby tumor cells can spread to organs beyond the first capillary bed downstream from the primary tumor. These results also show that a specific gene can affect the distribution of tumor cells within an animal, thereby influencing the global pattern of metastasis in that animal.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Howard Hughes Medical Institute
Massachusetts Institute of Technology. Department of Physics
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Mechanical Engineering
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1158/0008-5472.CAN-20-0212
