Establishment of human iPSC-based models for the study and targeting of glioma initiating cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA279406 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1929990.fastq.gz | Fastqsanger.gz | |||
| SRR1929991.fastq.gz | Fastqsanger.gz | |||
| SRR1929992.fastq.gz | Fastqsanger.gz | |||
| SRR1929993.fastq.gz | Fastqsanger.gz | |||
| SRR1929984.fastq.gz | Fastqsanger.gz |
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Project description:Gliomas can originate upon transformation of adult Neural Progenitor Cells (NPCs) to Tumor Initiating Cells (TICs). Studies on human Glioma TICs (GTICs) have focused on the use of primary tumors from which GTICs could be isolated. Therefore investigations on the driver events underlying NPC transformation and human glioma initiation remain limited to the use of human embryonic material. Here we report on the development of strategies for the modeling of human gliomagenesis based on the use of human induced Pluripotent Stem Cells (hiPSCs). Transformation of hiPSC-derived NPCs (iNPCs) by defined genetic alterations led to the establishment of tractable human GTIC models suitable for studying the early steps of gliomagenesis as well as for screening studies. Dysregulation of PI3K, MAPK and p53 signaling in iNPCs led to the acquisition of functional GTIC properties. In vivo transplantation led to the formation of highly aggressive, infiltrative and heterogeneous tumors upon limited dilutions and secondary transplantation, faithfully recapitulating gliomagenesis. Metabolic modulation by chemical approaches compromised GTIC viability. Pilot screening of 101 anti-cancer compounds identified 3 molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results demonstrate the potential of hiPSCs for the functional testing of putative driver mutations underlying human tumorigenesis and pave new avenues for the development of personalized cancer therapeutics.
2015-12-01 | GSE67283 | GEO
Project description:Gliomas can originate upon transformation of adult Neural Progenitor Cells (NPCs) to Tumor Initiating Cells (TICs). Studies on human Glioma TICs (GTICs) have focused on the use of primary tumors from which GTICs could be isolated. Therefore investigations on the driver events underlying NPC transformation and human glioma initiation remain limited to the use of human embryonic material. Here we report on the development of strategies for the modeling of human gliomagenesis based on the use of human induced Pluripotent Stem Cells (hiPSCs). Transformation of hiPSC-derived NPCs (iNPCs) by defined genetic alterations led to the establishment of tractable human GTIC models suitable for studying the early steps of gliomagenesis as well as for screening studies. Dysregulation of PI3K, MAPK and p53 signaling in iNPCs led to the acquisition of functional GTIC properties. In vivo transplantation led to the formation of highly aggressive, infiltrative and heterogeneous tumors upon limited dilutions and secondary transplantation, faithfully recapitulating gliomagenesis. Metabolic modulation by chemical approaches compromised GTIC viability. Pilot screening of 101 anti-cancer compounds identified 3 molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results demonstrate the potential of hiPSCs for the functional testing of putative driver mutations underlying human tumorigenesis and pave new avenues for the development of personalized cancer therapeutics.
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Project description:Gliomas can originate upon transformation of adult Neural Progenitor Cells (NPCs) to Tumor Initiating Cells (TICs). Studies on human Glioma TICs (GTICs) have focused on the use of primary tumors from which GTICs could be isolated. Therefore investigations on the driver events underlying NPC transformation and human glioma initiation remain limited to the use of human embryonic material. Here we report on the development of strategies for the modeling of human gliomagenesis based on the use of human induced Pluripotent Stem Cells (hiPSCs). Transformation of hiPSC-derived NPCs (iNPCs) by defined genetic alterations led to the establishment of tractable human GTIC models suitable for studying the early steps of gliomagenesis as well as for screening studies. Dysregulation of PI3K, MAPK and p53 signaling in iNPCs led to the acquisition of functional GTIC properties. In vivo transplantation led to the formation of highly aggressive, infiltrative and heterogeneous tumors upon limited dilutions and secondary transplantation, faithfully recapitulating gliomagenesis. Metabolic modulation by chemical approaches compromised GTIC viability. Pilot screening of 101 anti-cancer compounds identified 3 molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results demonstrate the potential of hiPSCs for the functional testing of putative driver mutations underlying human tumorigenesis and pave new avenues for the development of personalized cancer therapeutics.
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Project description:Transcriptome-wide analysis of CRISPR-edited iPSC-derived glioma models
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Project description:Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in ?90% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformed iNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiated derivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancer compounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.
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Project description:CRISPR-edited human induced pluripotent stem cell (iPSC)-derived glioma models provide a robust platform to investigate the biology of these aggressive tumors in an isogenic background or to test possible treatments in preclinical settings. We created iPSC12 lines that carry different combinations of glioma driver mutations using CRISPR/Cas9 genome editing technology, including TP53-/-, ATRX-/-, IDH1-R132H/WT, PTEN-/-, CDKN2A/B-/-, TERT promoter(TERTp) C228T/WT, MTAP-/-, and overexpression (OE) of EGFRvIII oncogenic isoform. Edited iPSCs were then differentiated into neural progenitor cells (NPC) using a small molecule protocol. We cultured the edited NPCs in 3D organoid with an FBS-containing differentiation medium. After 14 days, different genotypes of NPCs formed organoids were harvest and RNAs were isolated and subjected to RNA-seq analysis. To create an in vivo model system, NPCs with different genotypes were intracranially transplanted into athymic mice. Mice were sacrificed when pathologic symptoms developed resulting from tumor burden or 120 days post brain transplantation. RNAs were extracted from the tumor region of brain tissue sections and subjected to RNA-seq analysis. Our study showed that the iPSC-based model of gliomas displayed distinct mutation-dependent variation in transcriptome, which recapitulated the gene expression signatures of human gliomas.
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Project description:To identify factors involved in tumorigenicity of glioma-initiating cells (GICs), we compared gene expression in GIC-like cells with and without sox11 expression. We established sox11-expressing mouse glioma-initiating cell (GIC)-like cell line (NSCL61s), NSCL61s-sox11, which lost tumorigenicity when transplanted in vivo. We think that genes, which are differently expressed between NSCL61s and NSCL61s-sox11, would be new targets for glioma therapy.
2009-11-30 | E-GEOD-17076 | biostudies-arrayexpress
Project description:To identify factors involved in glioma-initiating cells (GICs), we compared gene expressions between GIC-like cells and non-GICs.
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Project description:To identify a novel miRNA that is aberrantly expressed in GICs, we analyzed differences in miRNA expression between the mouse GICs, NSCL61 and OPCL61, showing characteristic features of cancer stem cell, and their parental cells by miRNA microarrays. neural stem cells, glioma-initiating cells (GICs) from neural stem cells, oligodendrocyte precursor cells, glioma-initiating cells (GICs) from oligodendrocyte precursor cells.
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Project description:To identify factors involved in tumorigenicity of glioma-initiating cells (GICs), we compared gene expression in GIC-like cells with and without sox11 expression.
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