MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

RaeAnna 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 and Sudarshan Anand ()
Additional contact information
RaeAnna Wilson: Developmental and Cancer Biology, Oregon Health and Science University
Cristina Espinosa-Diez: Developmental and Cancer Biology, Oregon Health and Science University
Nathan Kanner: Developmental and Cancer Biology, Oregon Health and Science University
Namita Chatterjee: Developmental and Cancer Biology, Oregon Health and Science University
Rebecca Ruhl: Developmental and Cancer Biology, Oregon Health and Science University
Christina Hipfinger: Developmental and Cancer Biology, Oregon Health and Science University
Sunil J. Advani: University of California
Jie Li: University of California
Omar F. Khan: Institute for Medical Engineering and Science, David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Aleksandra Franovic: University of California
Sara M. Weis: University of California
Sushil Kumar: Developmental and Cancer Biology, Oregon Health and Science University
Lisa M. Coussens: Developmental and Cancer Biology, Oregon Health and Science University
Daniel G. Anderson: Institute for Medical Engineering and Science, David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Clark C. Chen: University of California
David A. Cheresh: University of California
Sudarshan Anand: Developmental and Cancer Biology, Oregon Health and Science University

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13597

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