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Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene\u00a0expression 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.<\/jats:p>","DOI":"10.1038\/s41598-024-56102-5","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T07:10:03Z","timestamp":1711523403000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Hypoxia drives shared and distinct transcriptomic changes in two invasive glioma stem cell lines"],"prefix":"10.1038","volume":"14","author":[{"given":"Valerie J.","family":"Marallano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Ughetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rut","family":"Tejero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidhanta","family":"Nanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohana","family":"Ramalingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Stalbow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirudh","family":"Sattiraju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarthi","family":"Ramakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Wojcinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Kesari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Tsankov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland H.","family":"Friedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"56102_CR1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.ccell.2017.06.003","volume":"32","author":"Q Wang","year":"2017","unstructured":"Wang, Q. et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 32, 42-56.e46. https:\/\/doi.org\/10.1016\/j.ccell.2017.06.003 (2017).","journal-title":"Cancer Cell"},{"key":"56102_CR2","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","volume":"17","author":"RG Verhaak","year":"2010","unstructured":"Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98\u2013110. https:\/\/doi.org\/10.1016\/j.ccr.2009.12.020 (2010).","journal-title":"Cancer Cell"},{"key":"56102_CR3","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","volume":"178","author":"C Neftel","year":"2019","unstructured":"Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. 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