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Patient\u2010derived cancer cell lines (PDCs) offer a scalable platform for mechanistic studies and therapeutic discovery, yet the extent to which culture dimensionality alters baseline molecular states and drug response in GCTB remains unclear. Here, we performed integrated transcriptomic, proteomic, and pharmacologic profiling of thirteen patient\u2010derived GCTB cell lines cultured under two\u2010dimensional (2D) monolayer and three\u2010dimensional (3D) spheroid conditions. RNA sequencing and data\u2010independent acquisition (DIA)\u2013based quantitative proteomics were conducted on paired cultures, and drug sensitivity was assessed using a panel of 221 anticancer agents. 3D culture reproducibly induced compact spheroid formation across all cell lines and was accompanied by broad remodeling of gene expression, protein abundance, and drug\u2010response profiles. Unsupervised analyses consistently demonstrated that samples clustered primarily by culture condition rather than by cell\u2010line identity at both the transcriptome and proteome levels. Although global trends were shared, a substantial fraction of molecules showed RNA\u2013protein discordance, indicating that transcriptomic changes alone do not fully explain culture\u2010dependent functional remodeling. Pathway analyses highlighted enrichment of extracellular matrix\u2013related processes, stress\u2010response programs, and metabolic regulation in 3D cultures, with several features more prominent at the protein level. Functionally, 3D culture generally reduced sensitivity to many agents while preserving compound\u2010dependent vulnerabilities. These results establish culture dimensionality as a key determinant of therapeutic susceptibility in GCTB PDCs and support incorporating proteome\u2010informed 3D models into translational pipelines to prioritize clinically relevant drug candidates and biomarkers.\n                  <\/jats:p>","DOI":"10.1002\/pmic.70136","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T11:20:08Z","timestamp":1777980008000},"page":"49-63","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrated Transcriptomic, Proteomic, and Pharmacologic Profiling of 2D and 3D Patient\u2010Derived GCTB Cell Lines Reveals Culture\u2010Dependent Drug Response Determinants"],"prefix":"10.1002","volume":"26","author":[{"given":"Yomogi","family":"Shiota","sequence":"first","affiliation":[{"name":"Division of Rare Cancer Research National Cancer Center  Chuo\u2010ku Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikumi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Zeon BioSolutions, Inc.  Kobe\u2010shi Hyogo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakura","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Knowledge Palette Inc.  Kawasaki\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumio","family":"Ohtsuki","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Faculty of Life Sciences Kumamoto University  Chuo\u2010ku Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Kondo","sequence":"additional","affiliation":[{"name":"Division of Rare Cancer Research National Cancer Center  Chuo\u2010ku Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2814"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.13"},{"key":"e_1_2_11_4_1","first-page":"204","article-title":"Curettage of Giant Cell Tumor of Bone. 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