ENDOTHELIAL INHIBITION OF THE GLYCOLYTIC ACTIVATOR PFKFB3 INDUCES TUMOR VESSEL NORMALIZATION, IMPAIRS METASTASIS AND IMPROVES CHEMOTHERAPY

Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) by targeting endothelial cells (ECs) is emerging as anti-cancer treatment. Here, we show that tumor ECs (TECs) have a hyper-glycolytic metabolism, shunting glycolytic intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell intra- and extravasation and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs and rendering glycolytic pericytes more quiescent; it also lowered the expression of cancer cell adhesion molecules in ECs. Additionally, PFKFB3-blockade treatment improved chemotherapy. Considering TEC metabolism for anti-cancer treatment might thus merit further attention.