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| Status |
Public on May 14, 2019 |
| Title |
Endothelial cell subtypes co-opt a TGFb/miR-30c-driven fibrinolytic pathway that supports tumor growth |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
In tumors, extravascular fibrin forms provisional scaffolds for angiogenesis but is degraded by fibrinolysis and replaced with collagen in a process that resembles wound healing. We report that fibrin-mediated angiogenesis is inhibited and tumor growth is delayed following postnatal deletion of TGFβR2 in the endothelium (TGFβR2iECKO). TGFβR2iECKO endothelial cells (ECs) fail to up-regulate the fibrinolysis inhibitor Serpine1/PAI-1 due, in part, to uncoupled TGFβ-mediated suppression of miR-30c. Bypassing TGFβR signaling with vascular tropic nanoparticles that deliver miR-30c AntagomiRs is sufficient to promote PAI-1-dependent tumor growth and increase fibrin abundance whereas miR-30c Mimics inhibit tumor growth and promote vascular-directed fibrinolysis in vivo. Using single cell RNA sequencing, we also show that subtypes of ECs in tumors show a spectrum of Serpine1 and uPar (urokinase receptor) expression suggesting functional diversity in ECs at the level of individual cells; furthermore, fresh EC isolates from lung and mammary tumor models have differential abilities to degrade fibrin and launch new vessel sprouts which is linked to their inverse expression patterns of miR-30c and Serpine1 (i.e. miR-30chiSerpine1lo ECs are poorly angiogenic and miR-30cloSerpine1hi ECs are highly angiogenic). Thus, EC subtypes co-opt physiological processes such as wound healing by subverting a previously uncharacterized vascular-directed fibrinolytic pathway that supports tumor growth.
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| Overall design |
Single-cell RNA-sequencing of tumor and normal endothelial cells
Researchers may wish to include the data series from GSE186467 which will increase the numbers of endothelial cells for analysis.
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| Contributor(s) |
McCann JV, Turner SD, Dudley A |
| Citation(s) |
30855280 |
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| Submission date |
Aug 22, 2018 |
| Last update date |
Feb 21, 2023 |
| Contact name |
Stephen Turner |
| Organization name |
Signature Science, LLC
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| Street address |
1670 Discovery Drive
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| City |
Charlottesville |
| State/province |
VA |
| ZIP/Postal code |
22911 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA487258 |
| SRA |
SRP158597 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE118904_rawcounts_negs.csv.gz |
5.2 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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