Endothelial miR-30c suppresses tumor growth via inhibition of TGF-[beta]-induced Serpinel

Introduction To support their growth, cancer cells recapitulate latent developmental or physiological processes including those important for tissue repair, wound healing, and angiogenesis; however, reactivation of these processes is typically [...]
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.sup.ERT2] [Tgfbr2.sup.fl/fl] mice ([Tgfbr2.sup.iECKO]mice). ECs from [Tgfbr2.sup.iECKO] 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 miR-30c 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.sup.hi] [Serpin1.sup.lo] ECs were poorly angiogenic and miR-[30c.sup.lo] Serpine[1.sup.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.