Il metabolismo dell'eme nelle cellule endoteliali controlla il profilo energetico delle cellule cancerose modulando il microambiente tumorale

The crosstalk among cancer cells and stromal cells within the tumor microenvironment has a prominent role in cancer progression. In this scenario, tumor-associated endothelial cells (TECs) significantly contribute to establish a pro-tumoral niche. Indeed, in addition to their angiogenic properties, TECs actively modulate cancer development by shuttling a selected pattern of factors and metabolites to surrounding cancer cells. The array of released metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Accordingly, TECs enhance glycolysis compared to normal endothelial cells in order to sustain their hyperproliferative and highly motile phenotype. Recent evidence highlights the involvement of heme in the modulation of TEC metabolic profile. Indeed, interfering with endothelial heme homeostasis by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) induces an oxidative metabolic shift. Based on these previous findings, we asked how these metabolic alterations might impact on the tumor microenvironment. To this purpose, the effects of endothelial FLVCR1a deficiency on cancer cell metabolism were evaluated both in vitro and in vivo. The present study shows that FLVCR1a targeting in TECs resulted in enhanced β-fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies intracellular accumulation in FLVCR1a-deficient TECs. Finally, TECs-derived ketone bodies could be secreted in the extracellular environment, thus inducing a metabolic rewiring in neighbouring cancer cells. Taken together, the results from this work strongly indicate that endothelial heme dynamics drive cancer cell metabolism by shaping the tumor microenvironment. Also, these data may contribute finding new metabolic vulnerabilities for cancer therapy.