MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Rae Anna Wilson, Cristina Espinosa-Diez, Nathan Kanner, Namita Chatterjee, Rebecca Ruhl, Christina Hipfinger, Sunil J. Advani, Jie Li, Omar F. Khan, Aleksandra Franovic, Sara M. Weis, Sushil Kumar, Lisa M. Coussens, Daniel G. Anderson, Clark C. Chen, David A. Cheresh, Sudarshan Anand

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.

Original languageEnglish (US)
Article number13597
JournalNature communications
Volume7
DOIs
StatePublished - Nov 25 2016

Bibliographical note

Funding Information:
We thank Patrick Flynn (OHSU) for useful discussions and help with tumour microenvironment profiling. We thank Joe Aguilera (UCSD) for help with the comet assays. We thank the OHSU Advanced Light Microscopy Core, Knight Cancer Institute Flow Cytometry Core and the Gene Profiling Shared Resource for technical help and useful discussions. S.A. is supported by US NIH grant R00HL112962 and Barbara-Ann Miller Dive for the Cure Award from the OHSU Knight Cancer Institute (2015-Dive-Knight-01). D.A.C. is supported by US NIH grant R01 HL57900.

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