{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:12:59Z","timestamp":1789506779714,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Glioblastoma (GBM) is characterized by pronounced transcriptional plasticity and a highly structured immune microenvironment, yet the molecular features associated with tumor-state transitions and immune remodeling remain incompletely understood. Methods: We used an integrative multi-omics framework to examine how secreted phosphoprotein 1 (SPP1) relates to tumor microenvironment organization in human gliomas. Results: Single-cell analyses associated SPP1 with myeloid populations, mesenchymal-like (MES-like) malignant states, inflammatory regulatory programs, and inferred ligand\u2013receptor co-expression patterns involving SPP1\u2013CD44 and SPP1\u2013integrin pairs. Spatial transcriptomic analyses showed that SPP1-high regions were enriched for estimated myeloid abundance, MES-like tumor signal, and ECM\/angiogenic programs, supporting an SPP1-associated spatial mesenchymal\u2013myeloid program in GBM. Computational perturbation analyses provided network-level support for SPP1\u2013CD44-associated stress-responsive programs. HPA immunohistochemistry provided tissue-level protein context for SPP1 and related mesenchymal\/receptor-associated components. Ivy GAP analysis showed enrichment of SPP1-associated features in core-like anatomic compartments, and CODEX spatial protein imaging provided antibody-panel-based contextual support for mesenchymal\u2013myeloid-associated features. In the TCGA-GBM cohort, elevated SPP1 expression and an SPP1-associated mesenchymal signature were associated with poorer overall survival. Conclusions: These findings support an inferential model in which SPP1 is associated with spatial mesenchymal\u2013myeloid organization in GBM and nominate SPP1-associated programs as candidate readouts of tumor plasticity, inflammatory myeloid remodeling, and spatial tumor microenvironment organization.<\/jats:p>","DOI":"10.3390\/genes17060610","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:09:07Z","timestamp":1779970147000},"page":"610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Multi-Omics Analysis Identifies an SPP1-Associated Spatial Mesenchymal\u2013Myeloid Program in Glioblastoma"],"prefix":"10.3390","volume":"17","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, West China Hospital of Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology, West China Hospital of Sichuan University, Chengdu 610041, China"},{"name":"Institute of Brain Science and Brain-Inspired Technology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0014-6873","authenticated-orcid":false,"given":"Zhen","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Neurology, West China Hospital of Sichuan University, Chengdu 610041, China"},{"name":"Institute of Brain Science and Brain-Inspired Technology, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_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","year":"2019","journal-title":"Cell"},{"key":"ref_2","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","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ccell.2017.06.003","article-title":"Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment","volume":"32","author":"Wang","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nn.4185","article-title":"The Role of Microglia and Macrophages in Glioma Maintenance and Progression","volume":"19","author":"Hambardzumyan","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ccr.2013.08.001","article-title":"Mesenchymal Differentiation Mediated by NF-\u03baB Promotes Radiation Resistance in Glioblastoma","volume":"24","author":"Bhat","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/nature08712","article-title":"The Transcriptional Network for Mesenchymal Transformation of Brain Tumours","volume":"463","author":"Carro","year":"2010","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12672-025-04273-6","article-title":"SPP1 Regulates Tumor Progression through Modulation of Signaling Pathways and the Tumor Microenvironment","volume":"17","author":"Feng","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1172\/JCI121266","article-title":"Osteopontin Mediates Glioblastoma-Associated Macrophage Infiltration and Is a Potential Therapeutic Target","volume":"129","author":"Wei","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"He, C., Sheng, L., Pan, D., Jiang, S., Ding, L., Ma, X., Liu, Y., and Jia, D. (2021). Single-Cell Transcriptomic Analysis Revealed a Critical Role of SPP1\/CD44-Mediated Crosstalk Between Macrophages and Cancer Cells in Glioma. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.779319"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fu, Y., Yi, Y., Shao, Y., Jiang, J., and Deng, Q. (2025). Single-Cell and Spatial Transcriptomic Insights into Glioma Cellular Heterogeneity and Metabolic Adaptations. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1561388"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1038\/s43018-022-00475-x","article-title":"A Single-Cell Atlas of Glioblastoma Evolution under Therapy Reveals Cell-Intrinsic and Cell-Extrinsic Therapeutic Targets","volume":"3","author":"Wang","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_12","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. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, Sensitive and Accurate Integration of Single-Cell Data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","article-title":"DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors","volume":"8","author":"McGinnis","year":"2019","journal-title":"Cell Syst."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-Based Analysis of Lung Single-Cell Sequencing Reveals a Transitional Profibrotic Macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9699","DOI":"10.1038\/s41467-024-53954-3","article-title":"Reconstructing the Regulatory Programs Underlying the Phenotypic Plasticity of Neural Cancers","volume":"15","author":"Larsson","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_18","first-page":"100141","article-title":"clusterProfiler 4.0: A Universal Enrichment Tool for Interpreting Omics Data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and Analysis of Cell-Cell Communication Using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41587-021-00830-w","article-title":"Robust Decomposition of Cell Type Mixtures in Spatial Transcriptomics","volume":"40","author":"Cable","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: Modeling Intercellular Communication by Linking Ligands to Target Genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100434","DOI":"10.1016\/j.patter.2022.100434","article-title":"scTenifoldKnk: An Efficient Virtual Knockout Tool for Gene Function Predictions via Single-Cell Gene Regulatory Network Perturbation","volume":"3","author":"Osorio","year":"2022","journal-title":"Patterns"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/pro.3987","article-title":"The Human Protein Atlas-Spatial Localization of the Human Proteome in Health and Disease","volume":"30","author":"Digre","year":"2021","journal-title":"Protein Sci."},{"key":"ref_24","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","year":"2018","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1016\/j.cell.2024.03.029","article-title":"Integrative Spatial Analysis Reveals a Multi-Layered Organization of Glioblastoma","volume":"187","author":"Greenwald","year":"2024","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"H\u00e4nzelmann, S., Castelo, R., and Guinney, J. (2013). GSVA: Gene Set Variation Analysis for Microarray and RNA-Seq Data. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-7"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: Digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ccell.2022.05.009","article-title":"Spatially Resolved Multi-Omics Deciphers Bidirectional Tumor-Host Interdependence in Glioblastoma","volume":"40","author":"Ravi","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41698-025-00920-x","article-title":"Exploring Tumor-Associated Macrophages in Glioblastoma: From Diversity to Therapy","volume":"9","author":"Zhao","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.ccell.2021.05.002","article-title":"Interactions between Cancer Cells and Immune Cells Drive Transitions to Mesenchymal-like States in Glioblastoma","volume":"39","author":"Hara","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1016\/j.cell.2022.04.038","article-title":"Glioma Progression Is Shaped by Genetic Evolution and Microenvironment Interactions","volume":"185","author":"Varn","year":"2022","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.ccell.2023.02.019","article-title":"Transcriptome Analysis Reveals Tumor Microenvironment Changes in Glioblastoma","volume":"41","author":"Hoogstrate","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/s41588-025-02168-4","article-title":"Deciphering the Longitudinal Trajectories of Glioblastoma Ecosystems by Integrative Single-Cell Genomics","volume":"57","author":"Spitzer","year":"2025","journal-title":"Nat. Genet."},{"key":"ref_34","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","year":"2025","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"0007","DOI":"10.34133\/cancomm.0007","article-title":"Hypoxia-Induced Osteopontin-Positive Glioma-Associated Macrophages Facilitate Glioma Mesenchymal Transition via NF-\u03baB Pathway Activation","volume":"46","author":"Yang","year":"2026","journal-title":"Cancer Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"216801","DOI":"10.1016\/j.canlet.2024.216801","article-title":"Hypoxia-Induced TREM1 Promotes Mesenchymal-like States of Glioma Stem Cells via Alternatively Activating Tumor-Associated Macrophages","volume":"590","author":"Dong","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1038\/s41467-026-69716-2","article-title":"A Spatially Resolved Human Glioblastoma Atlas Reveals Distinct Cellular and Molecular Patterns of Anatomical Niches","volume":"17","author":"Sonpatki","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/s41467-023-36707-6","article-title":"Spatial Transcriptomics Reveals Niche-Specific Enrichment and Vulnerabilities of Radial Glial Stem-like Cells in Malignant Gliomas","volume":"14","author":"Ren","year":"2023","journal-title":"Nat. Commun."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/610\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:20:47Z","timestamp":1779970847000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["genes17060610"],"URL":"https:\/\/doi.org\/10.3390\/genes17060610","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]}}}