Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines
Abstract Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is charac...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-56102-5 |
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| author | Valerie J. Marallano Mary E. Ughetta Rut Tejero Sidhanta Nanda Rohana Ramalingam Lauren Stalbow Anirudh Sattiraju Yong Huang Aarthi Ramakrishnan Li Shen Alexandre Wojcinski Santosh Kesari Hongyan Zou Alexander M. Tsankov Roland H. Friedel |
| author_facet | Valerie J. Marallano Mary E. Ughetta Rut Tejero Sidhanta Nanda Rohana Ramalingam Lauren Stalbow Anirudh Sattiraju Yong Huang Aarthi Ramakrishnan Li Shen Alexandre Wojcinski Santosh Kesari Hongyan Zou Alexander M. Tsankov Roland H. Friedel |
| author_sort | Valerie J. Marallano |
| collection | DOAJ |
| description | Abstract Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is characterized by high intertumoral (molecular subtypes) and intratumoral heterogeneity (cell states), and it is not well understood to what extent hypoxia triggers patient-specific gene responses and cellular diversity in GBM. Here, we surveyed eight patient-derived GBM stem cell lines for invasion phenotypes in 3D culture, which identified two GBM lines showing increased invasiveness in response to hypoxia. RNA-seq analysis of the two patient GBM lines revealed a set of shared hypoxia response genes concerning glucose metabolism, angiogenesis, and autophagy, but also a large set of patient-specific hypoxia-induced genes featuring cell migration and anti-inflammation, highlighting intertumoral diversity of hypoxia responses in GBM. We further applied the Shared GBM Hypoxia gene signature to single cell RNA-seq datasets of glioma patients, which showed that hypoxic cells displayed a shift towards mesenchymal-like (MES) and astrocyte-like (AC) states. Interestingly, in response to hypoxia, tumor cells in IDH-mutant gliomas displayed a strong shift to the AC state, whereas tumor cells in IDH-wildtype gliomas mainly shifted to the MES state. This distinct hypoxia response of IDH-mutant gliomas may contribute to its more favorable prognosis. Our transcriptomic studies provide a basis for future approaches to better understand the diversity of hypoxic niches in gliomas. |
| first_indexed | 2024-04-24T16:20:24Z |
| format | Article |
| id | doaj.art-dd8338919ea04009b7ac965cd5a4e33e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T16:20:24Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-dd8338919ea04009b7ac965cd5a4e33e2024-03-31T11:17:10ZengNature PortfolioScientific Reports2045-23222024-03-0114111210.1038/s41598-024-56102-5Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell linesValerie J. Marallano0Mary E. Ughetta1Rut Tejero2Sidhanta Nanda3Rohana Ramalingam4Lauren Stalbow5Anirudh Sattiraju6Yong Huang7Aarthi Ramakrishnan8Li Shen9Alexandre Wojcinski10Santosh Kesari11Hongyan Zou12Alexander M. Tsankov13Roland H. Friedel14Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiPacific Neuroscience Institute and Saint John’s Cancer Institute at Providence Saint John’s Health CenterPacific Neuroscience Institute and Saint John’s Cancer Institute at Providence Saint John’s Health CenterNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiAbstract Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is characterized by high intertumoral (molecular subtypes) and intratumoral heterogeneity (cell states), and it is not well understood to what extent hypoxia triggers patient-specific gene responses and cellular diversity in GBM. Here, we surveyed eight patient-derived GBM stem cell lines for invasion phenotypes in 3D culture, which identified two GBM lines showing increased invasiveness in response to hypoxia. RNA-seq analysis of the two patient GBM lines revealed a set of shared hypoxia response genes concerning glucose metabolism, angiogenesis, and autophagy, but also a large set of patient-specific hypoxia-induced genes featuring cell migration and anti-inflammation, highlighting intertumoral diversity of hypoxia responses in GBM. We further applied the Shared GBM Hypoxia gene signature to single cell RNA-seq datasets of glioma patients, which showed that hypoxic cells displayed a shift towards mesenchymal-like (MES) and astrocyte-like (AC) states. Interestingly, in response to hypoxia, tumor cells in IDH-mutant gliomas displayed a strong shift to the AC state, whereas tumor cells in IDH-wildtype gliomas mainly shifted to the MES state. This distinct hypoxia response of IDH-mutant gliomas may contribute to its more favorable prognosis. Our transcriptomic studies provide a basis for future approaches to better understand the diversity of hypoxic niches in gliomas.https://doi.org/10.1038/s41598-024-56102-5Glioblastomagliomahypoxia |
| spellingShingle | Valerie J. Marallano Mary E. Ughetta Rut Tejero Sidhanta Nanda Rohana Ramalingam Lauren Stalbow Anirudh Sattiraju Yong Huang Aarthi Ramakrishnan Li Shen Alexandre Wojcinski Santosh Kesari Hongyan Zou Alexander M. Tsankov Roland H. Friedel Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines Scientific Reports Glioblastoma glioma hypoxia |
| title | Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines |
| title_full | Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines |
| title_fullStr | Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines |
| title_full_unstemmed | Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines |
| title_short | Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines |
| title_sort | hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines |
| topic | Glioblastoma glioma hypoxia |
| url | https://doi.org/10.1038/s41598-024-56102-5 |
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