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

• Published in: The Journal of clinical investigation 2019-04, Vol.129 (4), p.1654
• Main Authors: McCann, James V, Xiao, Lin, Kim, Dae Joong, Khan, Omar F, Kowalski, Piotr S, Anderson, Daniel G, Pecot, Chad V, Azam, Salma H, Parker, Joel S, Tsai, Yihsuan S, Wolberg, Alisa S, Turner, Stephen D, Tatsumi, Kohei, Mackman, Nigel, Dudley, Andrew C
• Format: Article
• Language: English
• Subjects: Bone morphogenetic proteins; Breast cancer; Cancer cells; Cancer treatment; Endothelium; Fibrin; MicroRNA; Nanoparticles; Neovascularization; RNA; RNA sequencing; Transforming growth factors; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI123106.

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.