MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment
Author(s)Wilson, RaeAnna; Espinosa-Diez, Cristina; Kanner, Nathan; Chatterjee, Namita; Ruhl, Rebecca; Hipfinger, Christina; Advani, Sunil J.; Li, Jie; Franovic, Aleksandra; Weis, Sara M.; Kumar, Sushil; Coussens, Lisa M.; Chen, Clark C.; Cheresh, David A.; Anand, Sudarshan; Khan, Omar Fizal; Anderson, Daniel Griffith; ... Show more Show less
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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.
DepartmentInstitute for Medical Engineering and Science; David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Chemical Engineering
Nature Publishing Group
Wilson, RaeAnna, Cristina Espinosa-Diez, Nathan Kanner, Namita Chatterjee, Rebecca Ruhl, Christina Hipfinger, Sunil J. Advani, et al. “MicroRNA Regulation of Endothelial TREX1 Reprograms the Tumour Microenvironment.” Nature Communications 7 (November 25, 2016): 13597.
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