{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T12:23:21Z","timestamp":1794227001880,"version":"4.9.0"},"reference-count":36,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007414","name":"Qassim University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007414","id-type":"DOI","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01wsfe280","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>IDH-mutant gliomas show variable clinical behavior that may reflect transcriptional programs organized within tumor tissue. We evaluated two curated expression scores: a differentiation-loss\/Stem-NPC score (Axis1) and a mesenchymal\u2013hypoxia score (Axis2). Public single-cell RNA-sequencing data were used to characterize malignant-cell states, and the scores were evaluated in bulk clinical cohorts using portable within-sample ranks and covariate-adjusted Cox models. Axis2 was separated into non-overlapping mesenchymal-only and hypoxia-only components. Spatial organization was tested in Visium sections from 11 patients using patient-level inference and constrained null models. The mesenchymal-only component was associated with shorter overall survival in CGGA-693 (hazard ratio per standard deviation = 1.73, 95% confidence interval 1.43\u20132.11) and CGGA-325 (1.41, 1.10\u20131.79), although molecular adjustment attenuated the association in CGGA-325. It remained spatially autocorrelated (mean Moran\u2019s I = 0.297; p = 0.001). Removing gene overlap reduced its patient-level correlation with hypoxia from 0.798 to 0.254; residual co-organization was supported across all patients but not within either IDH subgroup. Axis1 showed no portable survival association. Thus, the mesenchymal component is outcome-associated and spatially organized, whereas the data do not establish hypoxia-driven organization, causality, or malignant-cell specificity.<\/jats:p>","DOI":"10.3390\/biology15181624","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:33:42Z","timestamp":1789479222000},"page":"1624","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Single-Cell, Spatial, and Bulk Transcriptomics Characterizes an Outcome-Associated, Spatially Organized Mesenchymal Program in IDH-Mutant Glioma"],"prefix":"10.3390","volume":"15","author":[{"given":"Kesavi Himabindhu","family":"Vuyyuru","sequence":"first","affiliation":[{"name":"Department of Bioinformatics, Vignan\u2019s Foundation for Science, Technology and Research, Vadlamudi 522213, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Vyshnavi","family":"Daggubati","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Vignan\u2019s Foundation for Science, Technology and Research, Vadlamudi 522213, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Abraham Peele","family":"Karlapudi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Vignan\u2019s Foundation for Science, Technology and Research, Vadlamudi 522213, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1095-8445","authenticated-orcid":false,"given":"Khurshid","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Health Informatics, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ccell.2018.04.011","article-title":"Biological Role and Therapeutic Potential of IDH Mutations in Cancer","volume":"34","author":"Waitkus","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41586-019-1775-1","article-title":"Longitudinal Molecular Trajectories of Diffuse Glioma in Adults","volume":"576","author":"Barthel","year":"2019","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature20123","article-title":"Single-Cell RNA-Seq Supports a Developmental Hierarchy in Human Oligodendroglioma","volume":"539","author":"Tirosh","year":"2016","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eaai8478","DOI":"10.1126\/science.aai8478","article-title":"Decoupling Genetics, Lineages, and Microenvironment in IDH-Mutant Gliomas by Single-Cell RNA-Seq","volume":"355","author":"Venteicher","year":"2017","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","article-title":"An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma","volume":"178","author":"Neftel","year":"2019","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s41467-022-28372-y","article-title":"Single-Cell Analysis of Human Glioma and Immune Cells Identifies S100A4 as an Immunotherapy Target","volume":"13","author":"Abdelfattah","year":"2022","journal-title":"Nat. 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