Endothelial cell subtypes co-opt a TGFb/miR-30c-driven fibrinolytic pathway that supports tumor growth

In tumors, extravascular fibrin forms provisional scaffolds for angiogenesis but is degraded by fibrinolysis and replaced with collagen in a process that resembles wound healing. We report that fibrin-mediated angiogenesis is inhibited and tumor growth is delayed following postnatal deletion of TGFßR2 in the endothelium (TGFßR2iECKO). TGFßR2iECKO endothelial cells (ECs) fail to up-regulate the fibrinolysis inhibitor Serpine1/PAI-1 due, in part, to uncoupled TGFß-mediated suppression of miR-30c. Bypassing TGFßR signaling with vascular tropic nanoparticles that deliver miR-30c AntagomiRs is sufficient to promote PAI-1-dependent tumor growth and increase fibrin abundance whereas miR-30c Mimics inhibit tumor growth and promote vascular-directed fibrinolysis in vivo. Using single cell RNA sequencing, we also show that subtypes of ECs in tumors show a spectrum of Serpine1 and uPar (urokinase receptor) expression suggesting functional diversity in ECs at the level of individual cells; furthermore, fresh EC isolates from lung and mammary tumor models have differential abilities to degrade fibrin and launch new vessel sprouts which is linked to their inverse expression patterns of miR-30c and Serpine1 (i.e. miR-30chiSerpine1lo ECs are poorly angiogenic and miR-30cloSerpine1hi ECs are highly angiogenic). Thus, EC subtypes co-opt physiological processes such as wound healing by subverting a previously uncharacterized vascular-directed fibrinolytic pathway that supports tumor growth. Overall design: Single-cell RNA-sequencing of tumor and normal endothelial cells Researchers may wish to include the data series from GSE186467 which will increase the numbers of endothelial cells for analysis.