McCann, James V and Xiao, Lin and Kim, Dae and Khan, Omar F and Kowalski, Piotr S and Anderson, Daniel G and Pecot, Chad V and Azam, Salma H and Parker, Joel S and Tsai, Yihsuan S and Wolberg, Alisa S and Turner, Stephen D and Tatsumi, Kohei and Mackman, Nigel and Dudley, Andrew C

2019

January

The Journal of Clinical Investigation

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

Validated

Altmetric: 44 ()

130

4

1654

1670

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-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKO mice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-ß-mediated suppression of miR-30c. Bypassing TGF-ß 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 Serpine1 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 Serpine1 (i.e., miR-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-ß, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.

10.1172/jci123106