Biochim Biophys Acta Gen Subj. 2020 Apr;1864(4):129540. doi: 10.1016/j.bbagen.2020.129540. Epub 2020 Jan 21.

A novel neuronal organoid model mimicking glioblastoma (GBM) features from induced pluripotent stem cells (iPSC).

Hwang JW¹, Loisel-Duwattez J², Desterke C¹, Latsis T¹, Pagliaro S¹, Griscelli F¹, Bennaceur-Griscelli A³, Turhan AG⁴.

Abstract

BACKGROUND:

Current experimental models using either human or mouse cell lines, are not representative of the complex features of GBM. In particular, there is no model to study patient-derived iPSCs to generate a GBM model. Overexpression of c-met gene is one of the molecular features of GBM leading to increased signaling via STAT3 phosphorylation. We generated an iPSC line from a patient with c-met mutation and we asked whether we could use it to generate neuronal-like organoids mimicking features of GBM.

METHODS:

We have generated iPSC-aggregates differentiating towards organoids. We analyzed them by gene expression profiling, immunostaining and transmission electronic microscopy analyses (TEM).

RESULTS:

Herein we describe that c-met-mutated iPSC aggregates spontaneously differentiate into dopaminergic neurons more rapidly than control iPSC aggregates in culture. Gene expression profiling of c-met-mutated iPSC aggregates at day +90 showed neuronal- and GBM-related genes, reproducing a genomic network described in primary human GBM. Comparative TEM analyses confirmed the enrichment of these structures in intermediate filaments and abnormal cilia, a feature described in human GBM. The c-met-mutated iPSC-derived organoids, as compared to controls expressed high levels of glial fibrillary acidic protein (GFAP), which is a typical marker of human GBM, as well as high levels of phospho-MET and phospho-STAT3. The use of temozolomide (TMZ) showed a preferential cytotoxicity of this drug in c-met-mutated neuronal-like organoids.

GENERAL SIGNIFICANCE:

This study shows the feasibility of generating "off-the shelf" neuronal-like organoid model mimicking GBM using c-met-mutated iPSC aggregates and its potential future use in research.

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