Gene signatures of quiescent glioblastoma cells reveal mesenchymal shift and interactions with niche microenvironment
| Autor: | Caroline C. Friedel, Jessica Tome-Garcia, Yuanshuo Wang, Michael Kluge, Roland H. Friedel, Nadejda M. Tsankova, Jung-Yi Lin, Nicolas Daviaud, Yong Huang, Rut Tejero, Bin Zhang, Hongyan Zou, Igor Katsyv |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Research paper Cell division Population Cell Fluorescent Antibody Technique Gene Expression Kaplan-Meier Estimate Biology General Biochemistry Genetics and Molecular Biology Extracellular matrix Transcriptome 03 medical and health sciences 0302 clinical medicine Genes Reporter Glioma Cell Line Tumor medicine Tumor Microenvironment Humans Gene Silencing Cell Self Renewal education education.field_of_study Brain Neoplasms Gene Expression Profiling Mesenchymal stem cell Cell Cycle Computational Biology General Medicine medicine.disease Immunohistochemistry Extracellular Matrix 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Neoplastic Stem Cells Stem cell Glioblastoma |
| Popis: | Background Glioblastoma (GBM), a highly malignant brain tumor, invariably recurs after therapy. Quiescent GBM cells represent a potential source of tumor recurrence, but little is known about their molecular underpinnings. Methods Patient-derived GBM cells were engineered by CRISPR/Cas9-assisted knock-in of an inducible histone2B-GFP (iH2B-GFP) reporter to track cell division history. We utilized an in vitro 3D GBM organoid approach to isolate live quiescent GBM (qGBM) cells and their proliferative counterparts (pGBM) to compare stem cell properties and therapy resistance. Gene expression programs of qGBM and pGBM cells were analyzed by RNA-Seq and NanoString platforms. Findings H2B-GFP-retaining qGBM cells exhibited comparable self-renewal capacity but higher therapy resistance relative to pGBM. Quiescent GBM cells expressed distinct gene programs that affect cell cycle control, metabolic adaptation, and extracellular matrix (ECM) interactions. Transcriptome analysis also revealed a mesenchymal shift in qGBM cells of both proneural and mesenchymal GBM subtypes. Bioinformatic analyses and functional assays in GBM organoids established hypoxia and TGFβ signaling as potential niche factors that promote quiescence in GBM. Finally, network co-expression analysis of TCGA glioma patient data identified gene modules that are enriched for qGBM signatures and also associated with survival rate. Interpretation Our in vitro study in 3D GBM organoids supports the presence of a quiescent cell population that displays self-renewal capacity, high therapy resistance, and mesenchymal gene signatures. It also sheds light on how GBM cells may acquire and maintain quiescence through ECM organization and interaction with niche factors such as TGFβ and hypoxia. Our findings provide a starting point for developing strategies to tackle the quiescent population of GBM. Fund National Institutes of Health (NIH) and Deutsche Forschungsgemeinschaft (DFG). |
| Databáze: | OpenAIRE |
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