Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1.

In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-Cre(ERT2) Tgfbr2(f1/f1) mice (Tgfbr2(IECK0) mice). ECs from Tgfbr2(IECK0) mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpinel, also known as PAI-1), due in part to uncoupled TGF-beta-mediated suppression of miR-30c. Bypassing TGF-beta signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1-dependent tumor growth and increased fibrin abundance, whereas miR30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpinel and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpinel (i.e., miR-30c(hi) Serpine1(10) ECs were poorly angiogenic and miR-30c(10)Serpine1(hi) ECs were highly angiogenic). Thus, by balancing Serpinel expression in ECs downstream of TGF-beta, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.