Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1
James V. McCann, … , Nigel Mackman, Andrew C. Dudley
James V. McCann, … , Nigel Mackman, Andrew C. Dudley
Published March 11, 2019
Citation Information: J Clin Invest. 2019;129(4):1654-1670. https://doi.org/10.1172/JCI123106.
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Research Article Oncology Vascular biology

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

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Figure 8

Concurrent miR-30clo Serpine1hi expression cumulatively predicts decreased patient survival in a large cohort of breast cancer patients.

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Concurrent miR-30clo Serpine1hi expression cumulatively predicts decreas...
(A) METABRIC data were downloaded from the Sage BioNetworks Synapse database (https://www.synapse.org/#!Synapse:syn1688369/wiki/27311). mRNA and miRNA expression data and clinical overall survival data from approximately 1285 patients were examined. SERPINE1 expression in a large cohort of breast cancer patients from a METRABRIC data set is shown. SERPINE1hi is defined as patients with SERPINE1 expression higher than the median SERPINE1 expression level. SERPINE1lo is defined as patients with SERPINE1 expression levels lower than or equal to the median SERPINE1 expression level. (B) miR-30c expression in breast cancer patients from the METABRIC data set. Definitions similar to those described above for SERPINE1 were used for patients’ miR-30chi and miR-30clo expression levels. (C) Concurrent expression of miR-30c and SERPINE1 in patients with breast cancer from the METRABIC data set. SERPINE1lo miR-30chi is defined as patients with SERPINE1 expression lower than the median SERPINE1 expression level and miR-30c expression higher than the median miR-30c expression level. SERPINE1hi miR-30clo is defined as patients with SERPINE1 expression higher than the median SERPINE1 expression level and miR-30c expression lower than the median miR-30c expression level. The remaining patients were defined as “others.” (D) SERPINE1 expression across breast cancer subtypes in The Cancer Genome Atlas Breast-Invasive Carcinoma (TCGA-BRCA) data set. TCGA breast cancer data were downloaded from the FireBrowse database (http://firebrowse.org/). mRNA and miRNA expression data and PAM50 subtypes were examined. (E) miR-30c expression across breast cancer subtypes in the TCGA-BRCA data set.