Characterization of a Novel Endothelial Network in Normal and Cancerous Tissues

ASPIRE AWARD (2021-2022)

Jessica Blackburn, PhD, University of Kentucky

Jessica Blackburn, PhD

When tumors reach a certain size, they need access to a blood supply to distribute oxygen, nutrients, and signaling molecules, which feed the tumor and allow it to grow and flourish. It is well established that tumor cells secrete Vascular Endothelial Growth Factor (VEGF), which is critical for angiogenesis, the sprouting of new blood vessels from existing ones. In theory, inhibiting vascular outgrowth deprives tumors of oxygen and nutrients, and could be a powerful therapy; but so far, VEGF inhibitors have largely failed in the clinic. Paradoxically, it is now understood that hypoxia, the lack of oxygen, may sometimes promote cancer cell metastasis and cancer stem cell self-renewal. However, tumors still need blood vessels to transport macromolecules critical for cellular function. If this is the case, why have VEGF blockers been so disappointing?

Using zebrafish models, Jessica Blackburn and her lab have identified a novel vascular structure that does not express the VEGF receptor (VEGFR) and, therefore, does not seem to rely on this factor for growth. Vessels of this new type of vasculature are smaller in diameter than oxygen-carrying erythrocytes, and are relatively permeable to blood plasma; thus, while they do not oxygenate tissues, they can deliver nutrients and macromolecules to tumors.

Blackburn and her group are defining the biology of this novel vascular network in both zebrafish and mammalian systems to assess its role in cancer hypoxia and progression, and to use high-throughput in vivo screening approaches to identify drugs capable of eliminating these vessels. The lab currently has one of the largest collections of vascular-related transgenic zebrafish in the world as well as easy access to a large suite of imaging equipment for both zebrafish and mice. The researchers will also identify biomarkers of VEGFR-negative microvasculature in zebrafish and mammalian tissues using RNA sequencing to distinguish VEGFR-negative vessels from other endothelial populations in normal and cancer tissue. By characterizing a novel type of cancer vasculature, this project has the potential to uncover more desirable drug targets and offer alternative cancer treatments.