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

Abstract

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-β-mediated suppression of miR-30c. Bypassing TGF-β 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-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.

• Authors: James V McCann, Lin Xiao, Dae Joong Kim, Omar F Khan, Piotr S Kowalski, Daniel G Anderson, Chad V Pecot, Salma H Azam, Joel S Parker, Yihsuan S Tsai, Alisa S Wolberg, Stephen D Turner, Kohei Tatsumi, Nigel Mackman, Andrew C Dudley
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 4 Pg. 1654-1670 (03 11 2019) ISSN: 1558-8238 [Electronic] United States
• PMID: 30855280 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• MicroRNAs
• Mirn30d microRNA, mouse
• Neoplasm Proteins
• Plasminogen Activator Inhibitor 1
• RNA, Neoplasm
• Transforming Growth Factor beta
• Receptor, Transforming Growth Factor-beta Type II
• Tgfbr2 protein, mouse

Topics

• Animals
• Endothelial Cells (metabolism, pathology)
• Female
• Gene Deletion
• Mammary Neoplasms, Experimental (blood supply, genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Neovascularization, Pathologic (genetics, metabolism, pathology)
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type II (deficiency, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)