{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:25:03Z","timestamp":1791224703874,"version":"4.1.0"},"reference-count":28,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bio Industrial Technology Development Program","award":["20018578"],"award-info":[{"award-number":["20018578"]}]},{"name":"Seoul National University Bundang Hospital Re-search Fund","award":["14-2024-0016"],"award-info":[{"award-number":["14-2024-0016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Cancer-associated fibroblasts (CAFs) are key components of the glioblastoma (GBM) microenvironment and contribute to tumor progression, immune evasion, and therapy resistance. However, their heterogeneity and clinical impact in GBM remain poorly defined. Methods: We performed an integrative transcriptomic analysis combining bulk and single-cell RNA sequencing (scRNA-seq) datasets to characterize CAF subtypes in GBM. Four CAF-associated transcriptional programs were defined based on canonical gene signatures: immune CAFs, myofibroblastic CAFs (myoCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). Prognostic relevance was assessed using survival analyses, and hub genes were identified through network analysis. Results: CAF subtype-specific gene signatures were significantly associated with poor overall survival. Single-cell analysis revealed spatial heterogeneity of CAF activation, with immune and inflammatory CAF markers enriched in low-stemness tumor cells. SYK was identified as a central hub gene shared across CAF subtypes, suggesting its role in stromal signaling. Conclusions: Our study reveals CAF subtype-associated patterns with prognostic and functional relevance in GBM. Targeting CAF subpopulations and key mediators such as SYK may represent a promising therapeutic strategy in GBM.<\/jats:p>","DOI":"10.3390\/cancers17243942","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T14:22:40Z","timestamp":1765376560000},"page":"3942","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dissecting CAF Heterogeneity in Glioblastoma Reveals Prognostic Subtypes and a Central Regulatory Role for Spleen Tyrosine Kinase (SYK)"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8397-1691","authenticated-orcid":false,"given":"Ji-Yong","family":"Sung","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul National University, Seongnam-si 13620, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7211-729X","authenticated-orcid":false,"given":"Kihwan","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul National University, Seongnam-si 13620, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1158\/1078-0432.CCR-23-0493","article-title":"Functional Contribution and Clinical Implication of Cancer-Associated Fibroblasts in Glioblastoma","volume":"30","author":"Galbo","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12943-023-01876-x","article-title":"Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment","volume":"22","author":"Ma","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12929-024-01099-2","article-title":"Cancer-associated fibroblasts as therapeutic targets for cancer: Advances, challenges, and future prospects","volume":"32","author":"Cao","year":"2025","journal-title":"J. Biomed. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12943-023-01860-5","article-title":"Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: New opportunities in cancer immunotherapy and advances in clinical trials","volume":"22","author":"Zhang","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e147087","DOI":"10.1172\/JCI147087","article-title":"Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects","volume":"133","author":"Jain","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/neuonc\/noy008","article-title":"SYK inhibition blocks proliferation and migration of glioma cells and modifies the tumor microenvironment","volume":"20","author":"Moncayo","year":"2018","journal-title":"Neuro Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: From bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7838583","DOI":"10.1155\/2022\/7838583","article-title":"The Role of Natural Products as Inhibitors of JAK\/STAT Signaling Pathways in Glioblastoma Treatment","volume":"2022","author":"Fahmideh","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1111\/jcmm.17268","article-title":"Overexpression of FOXD2-AS1 enhances proliferation and impairs differentiation of glioma stem cells by activating the NOTCH pathway via TAF-1","volume":"26","author":"Wang","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.bbrc.2023.04.100","article-title":"Targeting TAF1 with BAY-299 induces antitumor immunity in triple-negative breast cancer","volume":"665","author":"Zhang","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.tips.2024.08.006","article-title":"New insights into SYK targeting in solid tumors","volume":"45","author":"Joshi","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhou, Q., Wei, M., Shen, W., Huang, S., Fan, J., and Huang, H. (2022). SYK Is Associated with Malignant Phenotype and Immune Checkpoints in Diffuse Glioma. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.899883"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s41065-025-00548-8","article-title":"Integrated single-cell and bulk transcriptomic profiling reveals cancer-associated fibroblast heterogeneity in glioblastoma and establishes a clinically actionable prognostic model and preliminary experimental validation","volume":"162","author":"Zhang","year":"2025","journal-title":"Hereditas"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1038\/s12276-023-01013-0","article-title":"Cancer-associated fibroblasts: From basic science to anticancer therapy","volume":"55","author":"Yang","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hanzelmann, 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_18","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.stem.2016.05.010","article-title":"De Novo Prediction of Stem Cell Identity using Single-Cell Transcriptome Data","volume":"19","author":"Grun","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e70079","DOI":"10.1002\/ctm2.70079","article-title":"A subtype of cancer-associated fibroblast expressing syndecan-2 (SDC2) predicts survival and immune checkpoint inhibitor response in gastric cancer","volume":"14","author":"Sung","year":"2024","journal-title":"Clin. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sung, J.Y., and Cheong, J.H. (2021). Pan-Cancer Analysis Reveals Distinct Metabolic Reprogramming in Different Epithelial-Mesenchymal Transition Activity States. Cancers, 13.","DOI":"10.3390\/cancers13081778"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1347","DOI":"10.1002\/ctm2.1347","article-title":"Gene signature related to cancer stem cells and fibroblasts of stem-like gastric cancer predicts immunotherapy response","volume":"13","author":"Sung","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s12672-024-01314-4","article-title":"A cancer-associated fibroblasts related risk score (CAFscore) helps to guide prognosis and personal treatment for Glioblastoma","volume":"15","author":"Wu","year":"2024","journal-title":"Discov. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/s43018-022-00411-z","article-title":"Cancer-associated fibroblasts in the single-cell era","volume":"3","author":"Lavie","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e34526","DOI":"10.1016\/j.heliyon.2024.e34526","article-title":"Multi-omics reveals the impact of cancer-associated fibroblasts on the prognosis and treatment response of adult diffuse highest-grade gliomas","volume":"10","author":"Zhang","year":"2024","journal-title":"Heliyon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1186\/s13287-024-04022-6","article-title":"Transcriptional landscape of the interaction of human Mesenchymal Stem Cells with Glioblastoma in bioprinted co-cultures","volume":"15","author":"Oliver","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/1476-4598-9-168","article-title":"Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts","volume":"9","author":"Haubeiss","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/s41420-024-01958-9","article-title":"Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: Insights into apoptosis, autophagy, ferroptosis, and pyroptosis","volume":"10","author":"Chen","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.csbj.2021.12.010","article-title":"Unraveling unique and common cell type-specific mechanisms in glioblastoma multiforme","volume":"20","author":"Fathima","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/24\/3942\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T14:27:13Z","timestamp":1765376833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/24\/3942"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":28,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cancers17243942"],"URL":"https:\/\/doi.org\/10.3390\/cancers17243942","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]}}}