title: MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment.
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.
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: RaeAnna
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Espinosa-Diez
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Kanner
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ruhl
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Hipfinger
authors.affiliation: Department of Radiation Medicine and Applied Sciences, University of California, San Diego, California 92093, USA.
authors.forename: Sunil J
authors.initials: SJ
authors.lastname: Advani
authors.affiliation: Department of Neurosurgery, University of California, San Diego, California 92093, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Omar F
authors.identifier: http://orcid.org/0000-0003-3811-2369
authors.initials: OF
authors.lastname: Khan
authors.affiliation: 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.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Franovic
authors.affiliation: 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.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens
authors.affiliation: 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.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Department of Neurosurgery, University of California, San Diego, California 92093, USA.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Science University, Portland, Oregon 97229, USA.
authors.forename: Sudarshan
authors.identifier: http://orcid.org/0000-0002-4969-6884
authors.initials: S
authors.lastname: Anand
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics* / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism
chemical_list: C544749:MIRN103 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D019014:fas Receptor; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1