Project description:To identify endothelial-derived factors that may instructively drive cancer metastasis, we generated a new mouse model that allows endothelial-specific ribosomal tagging. We crossed the RiboTag (Rpl22fl/flHA) mice with the endothelial inducible Cre line Cdh5(PAC)-CreERT2 mice. Endothelial derived ribosome-associated mRNA-sequencing was performed from highly metastatic B16F10 and poorly metastatic B16F0 tumours.
Project description:To identify endothelial-derived factors that may instructively drive cancer metastasis, we generated a new mouse model that allows endothelial-specific ribosomal tagging. We crossed the RiboTag (Rpl22fl/flHA) mice with the endothelial inducible Cre line Cdh5(PAC)-CreERT2 mice. Endothelial derived ribosome-associated mRNA-sequencing was performed from highly metastatic B16F10 and poorly metastatic B16F0 tumours.
Project description:To identify endothelial-derived factors that may instructively drive cancer metastasis, we generated a new mouse model that allows endothelial-specific ribosomal tagging. We crossed the RiboTag (Rpl22fl/flHA) mice with the endothelial inducible Cre line Cdh5(PAC)-CreERT2 mice. Endothelial derived ribosome-associated mRNA-sequencing was performed from highly metastatic B16F10 and poorly metastatic B16F0 tumours.
Project description:Extracellular vesicles released by tumors (tEVs) disseminate via circulatory networks and promote microenvironmental changes in distant organs favoring metastatic seeding. Despite their abundance in the bloodstream, how hemodynamics affect the function of circulating tEVs remains unsolved. We experimentally tuned flow profiles in vitro (microfluidics) and in vivo (zebrafish) and demonstrated that efficient uptake of tEVs occurs in endothelial cells subjected to capillary-like hemodynamics. Such flow profiles partially reroute internalized tEVs towards non-acidic and non-degradative Rab14-positive endosomes, at the expense of lysosomes, suggesting that endothelial mechanosensing diverts tEVs from degradation. Subsequently, tEVs promote the expression of pro-angiogenic transcription factors in flow-stimulated endothelial cells and favor vessel sprouting in zebrafish. Altogether, we demonstrate that capillary-like flow profiles potentiate the pro-tumoral function of circulating tEVs by promoting their uptake and rerouting their trafficking. We propose that tEVs contribute to pre-metastatic niche formation by exploiting endothelial mechanosensing in specific vascular regions with permissive hemodynamics. This set of experiments represents RNAseq of HUVEC cells subjected to 400 µm/s flow versus no flow (static conditon).
Project description: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.