Human tissue engineering allows the identification of active miRNA regulators of glioblastoma aggressiveness.
Glioblastoma multiforme (GBM) is among the most aggressive cancers associated with massive infiltration of peritumoral parenchyma by migrating tumor cells. The infiltrative nature of GBM cells, the intratumoral heterogeneity concomitant with redundant signaling pathways likely underlie the inability of conventional and targeted therapies to achieve long-term remissions. In this respect, microRNAs (miRNAs), which are endogenous small non-coding RNAs that play a role in cancer aggressiveness, emerge as possible relevant prognostic biomarkers or therapeutic targets for treatment of malignant gliomas. We previously described a tissue model of GBM developing into a stem cell-derived human Engineered Neural Tissue (ENT) that allows the study of tumor/host tissue interaction. Combined with high throughput sequencing analysis, we took advantage of this human and integrated tissue model to understand miRNAs regulation. Three miRNAs (miR-340, -494 and -1293) active on cell proliferation, adhesion to extracellular matrix and tumor cell invasion were identified in GBM cells developing within ENT, and also confirmed in GBM biopsies. The components of miRNAs regulatory network at the transcriptional and the protein level have been also revealed by whole transcriptome analysis and Tandem Mass Tag in transfected GBM cells. Notably, miR-340 has a clinical relevance and modulates the expression of miR-494 and -1293, emphasizing its biological significance. Altogether, these findings demonstrate that human tissue engineering modeling GBM development in neural host tissue is a suitable tool to identify active miRNAs. Collectively, our study identified miR-340 as a strong modulator of GBM aggressiveness which may constitute a therapeutic target for treatment of malignant gliomas.
Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Switzerland. Electronic address: Erika.cosset@unige.ch.
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Cosset
Swiss Institute of Bioinformatics, Geneva, Switzerland.
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Petty
Laboratory of Tumor Immunology, Centre of Oncology, Geneva University Hospitals, University of Geneva, Switzerland.
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Dutoit
Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Switzerland.
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Tirefort
Fasteris SA, Plan-les-Ouates, Switzerland.
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Otten-Hernandez
Fasteris SA, Plan-les-Ouates, Switzerland.
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Farinelli
Laboratory of Tumor Immunology, Centre of Oncology, Geneva University Hospitals, University of Geneva, Switzerland.
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Dietrich
Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Switzerland; Department of Human Protein Sciences, Faculty of Medicine, University of Geneva, Switzerland. Electronic address: Olivier.preynat-seauve@hcuge.ch.
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Preynat-Seauve
D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D058953:Neural Stem Cells / Q000473:pathology*; D015398:Signal Transduction; D023822:Tissue Engineering / Q000379:methods*
C000589719:MIRN1293 microRNA, human; C570046:MIRN340 microRNA, human; C547168:MIRN494 microRNA, human; D035683:MicroRNAs
Glioblastoma; MicroRNAs; Nerve tissue engineering; Ultra-deep sequencing