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

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.

Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

“…Extracellular vesicles have been involved in intercellular communications within GBM, by carrying metabolites, nucleotides and proteins able to affect the behavior of cancerous as well as noncancerous cells composing the tumor [6,21]. Our experimental results are coherent with our modeling results that place ELOVL2 at the core of the metabolic pathways essential for sustaining GBM cell tumorigenicity.…”

Application of the microRNA‐302/367 cluster in cancer therapy

“…Cross‐talk between ceRNAs adds a new dimension to the regulation of miRNA expression and function. A large number of miR‐302/367 family members can be encapsulated by exosomes and internalized by adjacent glioblastoma cells, thereby affecting cellular biological behavior . The regulation of miR‐302/367 cluster expression in the nucleus, cytoplasm, and extracellular space and the intercellular exchange of miR‐302/367 cluster members through exosomes contribute to the biological significance of the differential expression of this cluster (Figure ).…”

“…One study on HCC showed that the E2F7/AKT/β‐catenin/CCND1 pathway is regulated by miR‐302a/d, which can inhibit the stemness of liver CSCs and the proliferation of tumor cells . Furthermore, some evidence from a glioblastoma mouse model showed that the cell‐to‐cell transfer of miR‐302/367 can result in the inhibition of CXCR4/SDF1, SHH, CCND, CCNA and E2F1, which are targets of miR‐302/367 …”

RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials

“…They intracranially implanted patient-derived glioblastoma stem-like cells (GSC) both naïve and ectopically expressing miR-302–367, a miRNA cluster with a tumor suppressive biological role [66]. MiRNA-containing exosomes were naturally released from the GSC cells and the miRNA molecules were taken up by the naïve neighboring GSC cells; which provoked a reduction in tumor growth.…”

“…They concluded that these miRNAs are transferred from cell-to-cell by exosomes affecting the stemness, proliferation, and tumorigenicity of both the exosome-releasing and exosome-acquiring cells. The authors of this study suggest that using cell-based therapies could be an effective method to deliver miRNA-containing exosomes as a new therapeutic alternative for GBM treatment [66]. In another study, Teplyuk et al used the orthotopic xenograft mouse model to evaluate the therapeutic effect of a miR-10b antisense oligonucleotide (ASO) in patient-derived GSCs.…”