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; Sudarshan Anand

doi:10.1038/ncomms13597

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Nat Commun. 2016 Nov 25:7:13597. doi: 10.1038/ncomms13597.

Authors

RaeAnna Wilson¹, Cristina Espinosa-Diez¹, Nathan Kanner¹, Namita Chatterjee¹, Rebecca Ruhl¹, Christina Hipfinger¹, Sunil J Advani², Jie Li³, Omar F Khan⁴, Aleksandra Franovic⁵, Sara M Weis⁵, Sushil Kumar¹, Lisa M Coussens¹, Daniel G Anderson⁴, Clark C Chen³, David A Cheresh⁵, Sudarshan Anand¹

Affiliations

¹ Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
² Department of Radiation Medicine and Applied Sciences, University of California, San Diego, California 92093, USA.
³ Department of Neurosurgery, University of California, San Diego, California 92093, USA.
⁴ Department of Chemical Engineering, Institute for Medical Engineering and Science, David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
⁵ Department of Pathology at the UC San Diego Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California 92037, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Down-Regulation
Exodeoxyribonucleases / genetics*
Exodeoxyribonucleases / metabolism
Female
Gene Expression Regulation, Neoplastic
Human Umbilical Vein Endothelial Cells
Humans
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / administration & dosage
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasms / genetics*
Neoplasms / immunology
Neoplasms / pathology
Neoplasms / therapy
Neovascularization, Pathologic / genetics*
Neovascularization, Pathologic / pathology
Neovascularization, Pathologic / radiotherapy
Phosphoproteins / genetics*
Phosphoproteins / metabolism
RNA, Small Interfering / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
Tumor Microenvironment / genetics*
Tumor Microenvironment / radiation effects
Xenograft Model Antitumor Assays
fas Receptor / metabolism

Substances

MIRN103 microRNA, human
MicroRNAs
Phosphoproteins
RNA, Small Interfering
Receptors, TNF-Related Apoptosis-Inducing Ligand
fas Receptor
Exodeoxyribonucleases
three prime repair exonuclease 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding