{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:50:15Z","timestamp":1791442215885,"version":"4.3.3"},"reference-count":19,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24H00037"],"award-info":[{"award-number":["JP24H00037"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP25ama221532h0002"],"award-info":[{"award-number":["JP25ama221532h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pathology International"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Glioblastoma,\n                    <jats:italic>IDH<\/jats:italic>\n                    \u2010wildtype, is the most common and malignant adult\u2010type diffuse glioma. It is characterized by extensive heterogeneity and poor prognosis. Recent single\u2010cell RNA\u2010sequencing studies have revealed distinct transcriptional programs that define cellular states such as astrocyte\u2010like, mesenchymal\u2010like, neural\u2010progenitor\u2010cell\u2010like, and oligodendrocyte\u2010progenitor\u2010cell\u2010like. However, their spatial context remains unclear because of the limitations of single\u2010cell and spot\u2010based spatial transcriptomics. In the present study, we applied a single\u2010cell molecular classification of glioblastoma to a spatial transcriptomic analysis using the Xenium in situ platform. A custom gene panel comprising 366 genes, including 100 additional genes beyond the predesigned central nervous system panel, was designed to enable high\u2010resolution, cell\u2010level analysis. We constructed reduced modules derived from the Neftel et al. classification and validated their reproducibility across public single\u2010cell datasets, achieving approximately 80% concordance with the original modules. In three cases of glioblastoma,\n                    <jats:italic>IDH<\/jats:italic>\n                    \u2010wildtype, spatial transcriptomic profiling revealed regional variations in transcriptional states; cellular tumor regions, regions of pseudopalisading necrosis were significantly enriched in reduced neural\u2010progenitor\u2010like\u2010cells subtype 1, and reduced mesenchymal\u2010like\u2010cells subtype 2, respectively. Our data indicate that the novel reduced module provides a framework for investigating single\u2010cell molecular states within a tissue context in glioblastoma.\n                  <\/jats:p>","DOI":"10.1111\/pin.70184","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:02:32Z","timestamp":1791439352000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reduced Gene Module for Spatial Transcriptomics Recapitulates Single\u2010Cell Molecular Classifications of Glioblastoma"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9682-9328","authenticated-orcid":false,"given":"Koki","family":"Ise","sequence":"first","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3474-2646","authenticated-orcid":false,"given":"Zen\u2010ichi","family":"Tanei","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology Hokkaido University Hospital Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2907-8704","authenticated-orcid":false,"given":"Takeru","family":"Kuwabara","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9921-0988","authenticated-orcid":false,"given":"Jintao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-9684","authenticated-orcid":false,"given":"Yoshitaka","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6145-395X","authenticated-orcid":false,"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8848-9415","authenticated-orcid":false,"given":"Hirokazu","family":"Sugino","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken\u2010ichi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Nakamura Memorial Hospital Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5400-5905","authenticated-orcid":false,"given":"Masumi","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"},{"name":"Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6470-3301","authenticated-orcid":false,"given":"Shinya","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Cancer Pathology, Faculty of Medicine Hokkaido University Sapporo Japan"},{"name":"Department of Surgical Pathology Hokkaido University Hospital Sapporo Japan"},{"name":"Hokkaido University Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.cell.2015.12.028","article-title":"Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma","volume":"164","author":"Ceccarelli M.","year":"2016","journal-title":"Cell"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1007\/s00401-018-1913-0","article-title":"Cimpact\u2010Now Update 3: Recommended Diagnostic Criteria for \u201cDiffuse Astrocytic Glioma, Idh\u2010Wildtype, With Molecular Features of Glioblastoma, Who Grade IV","volume":"136","author":"Brat D. J.","year":"2018","journal-title":"Acta Neuropathologica"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma","volume":"352","author":"Stupp R.","year":"2005","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/nrc2818","article-title":"Targeting Brain Cancer: Advances in the Molecular Pathology of Malignant Glioma and Medulloblastoma","volume":"10","author":"Huse J. T.","year":"2010","journal-title":"Nature Reviews Cancer"},{"key":"e_1_2_12_6_1","first-page":"299","article-title":"Management of Glioblastoma: State of the Art and Future Directions","volume":"70","author":"Tan A. C.","year":"2020","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.stem.2016.11.003","article-title":"Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance","volume":"20","author":"Liau B. B.","year":"2017","journal-title":"Cell Stem Cell"},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1","volume":"17","author":"Verhaak R. G. W.","year":"2010","journal-title":"Cancer Cell"},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ccell.2017.06.003","article-title":"Tumor Evolution of Glioma\u2010Intrinsic Gene Expression Subtypes Associates With Immunological Changes in the Microenvironment","volume":"32","author":"Wang Q.","year":"2017","journal-title":"Cancer Cell"},{"key":"e_1_2_12_10_1","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1126\/science.aaf2666","article-title":"An Anatomic Transcriptional Atlas of Human Glioblastoma","volume":"360","author":"Puchalski R. B.","year":"2018","journal-title":"Science"},{"key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1126\/science.1254257","article-title":"Single\u2010Cell RNA\u2010Seq Highlights Intratumoral Heterogeneity in Primary Glioblastoma","volume":"344","author":"Patel A. P.","year":"2014","journal-title":"Science"},{"key":"e_1_2_12_12_1","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 C.","year":"2019","journal-title":"Cell"},{"key":"e_1_2_12_13_1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s41467-022-28372-y","article-title":"Single\u2010Cell Analysis of Human Glioma and Immune Cells Identifies S100A4 as An Immunotherapy Target","volume":"13","author":"Abdelfattah N.","year":"2022","journal-title":"Nature Communications"},{"key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/s41586-025-08633-8","article-title":"Programs, Origins and Immunomodulatory Functions of Myeloid Cells in Glioma","volume":"640","author":"Miller T. E.","year":"2025","journal-title":"Nature"},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary Learning for Integrative, Multimodal and Scalable Single\u2010Cell Analysis","volume":"42","author":"Hao Y.","year":"2024","journal-title":"Nature Biotechnology"},{"key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41587-020-00795-2","article-title":"Delineating Copy Number and Clonal Substructure in Human Tumors From Single\u2010Cell Transcriptomes","volume":"39","author":"Gao R.","year":"2021","journal-title":"Nature Biotechnology"},{"key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1038\/s41467-020-17186-5","article-title":"Single\u2010Cell Rna\u2010Seq Reveals That Glioblastoma Recapitulates a Normal Neurodevelopmental Hierarchy","volume":"11","author":"Couturier C. P.","year":"2020","journal-title":"Nature Communications"},{"key":"e_1_2_12_18_1","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/s41588-025-02167-5","article-title":"The Multilayered Transcriptional Architecture of Glioblastoma Ecosystems","volume":"57","author":"Nomura M.","year":"2025","journal-title":"Nature Genetics"},{"key":"e_1_2_12_19_1","doi-asserted-by":"crossref","DOI":"10.1093\/noajnl\/vdad142","article-title":"Spatial Architecture of High\u2010Grade Glioma Reveals Tumor Heterogeneity Within Distinct Domains","volume":"5","author":"Moffet J. J. D.","year":"2023","journal-title":"Neuro\u2010Oncology Advances"},{"key":"e_1_2_12_20_1","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1038\/s41592-024-02496-z","article-title":"Probe Set Selection for Targeted Spatial Transcriptomics","volume":"21","author":"Kuemmerle L. B.","year":"2024","journal-title":"Nature Methods"}],"container-title":["Pathology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pin.70184","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/pin.70184","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pin.70184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:02:35Z","timestamp":1791439355000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/pin.70184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":19,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/pin.70184"],"URL":"https:\/\/doi.org\/10.1111\/pin.70184","archive":["Portico"],"relation":{},"ISSN":["1320-5463","1440-1827"],"issn-type":[{"value":"1320-5463","type":"print"},{"value":"1440-1827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70184"}}