Simply the B(r)east: endothelial cell heterogeneity in health and disease. Single cell analysis of transcriptomes in endothelial cells.

Traditional anti-angiogenesis strategies attempt to prune tumor vessels. However, their success is restricted by toxicity and resistance. There is thus an unmet need for new anti-angiogenic strategies with fundamentally distinct mechanisms. An alternative therapeutic paradigm is tumor vessel normalization (TVN). By healing disorganized vessels, TVN improves perfusion and oxygenation, tightens the leaky vascular wall, thus reducing metastasis and enhancing chemotherapy delivery and responses. The host laboratory showed that haplodeficiency of the glycolytic activator PFKFB3 in endothelial cells or treatment with the PFKFB3 inhibitor 3PO induces TVN, reduces metastasis and improves the delivery of and response to cisplatin. Here, I propose to broaden this concept to anti-cancer immunotherapy. Given the emerging importance of immunotherapy, I will investigate whether TVN induced by targeting EC glycolysis also improves intratumoral delivery and activation of immune cells, and therefore has an increased efficacy. Moreover, I will evaluate whether TVN affects the metabolism of cancer cells and whether targeting these metabolic drivers enhances the vulnerability of cancer cells to immunotherapy. This SB PhD proposal promises to yield entirely novel insights in the therapeutic potential of new metabolic targets which may improve immune checkpoint blockade. My PhD application will be crucial for my future as physician-scientist and to develop as an independent scientist.

Publication year:2021

Accessibility:Embargoed