Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth

Mohamed Fareh, Fabien Almairac, Laurent Turchi, Fanny Burel-Vandenbos, Philippe Paquis, Denys Fontaine, Sandra Lacas-Gervais, Marie Pierre Junier, Hervé Chneiweiss, Thierry Virolle

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Abstract

Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-To-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

Original languageEnglish
Article numbere2713
Number of pages11
JournalCell Death and Disease
Volume8
Issue number3
DOIs
Publication statusPublished - 2017

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