Endothelial mitochondria: enigmatic function and potential target for tumor anti-angiogenesis?

Blood vessel formation (angiogenesis) promotes tumor growth and metastasis. Current antiangiogenic therapies target endothelial growth factors, but suffer from limited efficacy. Also, since tumor vessels are structurally and functionally abnormal (which impairs perfusion), pruning them by anti-angiogenic therapy may create a more hostile nutrient-deprived milieu, promoting cancer cell escape and dissemination. A novel paradigm is to “normalize” the tumor vessels to improve perfusion, which reduces metastasis and improves chemotherapy. The host lab pioneered the novel concept that endothelial cells (ECs) reprogram their metabolism to form new blood vessels. They discovered an important role of glycolysis and fatty acid oxidation in angiogenesis, and that blocking these pathways inhibits pathological angiogenesis. However, the role of mitochondria in ECs during angiogenesis remains unknown. Using a multidisciplinary
approach involving EC cultures and genetic mouse models with dysfunctional mitochondria in ECs, I will study the role of mitochondria in tumor angiogenesis and vessel normalization, characterize the underlying cellular and metabolic mechanisms, and explore which metabolites are altered upon EC mitochondrial dysfunction, as this may identify novel metabolic targets for future antiangiogenesis approaches in cancer therapy. This project will yield the first conclusive in vivo genetic evidence about the role and importance of mitochondria for (tumor) angiogenesis.