{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T05:26:20Z","timestamp":1786771580978,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017958","name":"Health Commission of Hubei Province","doi-asserted-by":"crossref","award":["WJ2023Z011"],"award-info":[{"award-number":["WJ2023Z011"]}],"id":[{"id":"10.13039\/100017958","id-type":"DOI","asserted-by":"crossref"}]},{"award":["WJ2023Z011"],"award-info":[{"award-number":["WJ2023Z011"]}],"id":[{"id":"https:\/\/ror.org\/02g4yc525","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Traditional Chinese Medicine from Hubei Provincial Administration of Traditional Chinese Medicine","award":["ZY2023Z005"],"award-info":[{"award-number":["ZY2023Z005"]}]},{"name":"National Cancer Center Climbing Fund","award":["NCC201917A01"],"award-info":[{"award-number":["NCC201917A01"]}]},{"DOI":"10.13039\/501100018806","name":"Department of Science and Technology of Hubei Province","doi-asserted-by":"crossref","award":["2022ACA005"],"award-info":[{"award-number":["2022ACA005"]}],"id":[{"id":"10.13039\/501100018806","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Antibody\u2013drug conjugates (ADCs) targeting HER2 (encoded by ERBB2), Trop2 (TACSTD2), and Nectin-4 (NECTIN4) have demonstrated clinical activity in bladder cancer. However, the co-expression relationships among these three targets at both the transcriptomic and protein levels, and their spatial organization within the tumor microenvironment, remain incompletely characterized. To address this, we performed a multi-platform, multi-resolution analysis integrating ten bulk RNA-seq datasets (n = 1628 samples), six spatial transcriptomics datasets (10x Visium and Visium HD, n = 31 specimens), and multiplex immunofluorescence (mIF) staining on three paired tumor\u2013adjacent normal bladder specimens. Pairwise Pearson correlation analyses were conducted for ERBB2, TACSTD2, and NECTIN4 across bulk transcriptomes and spatial compartments (tumor core, interface, and stroma). High-resolution co-expression hotspot mapping was performed using Visium HD data. Preliminary protein-level evidence was obtained using mIF, with quantitative three-dimensional surface plot reconstructions illustrating the spatial distribution of marker co-expression. Given the limited number of specimens (three paired tumor\u2013normal samples), these findings should be regarded as exploratory and illustrative rather than definitive validation. Moderate-to-strong positive correlations among the three genes were consistently observed across all ten bulk datasets, with the strongest association between TACSTD2 and NECTIN4 (Pearson r up to 0.969). Spatial transcriptomic analyses recapitulated these positive correlations across all histopathological compartments, with the tumor core generally exhibiting the highest coefficients. No consistent spatial gradient was observed, indicating preservation of co-expression across tissue niches. Visium HD analysis confirmed positive pairwise correlations and identified discrete co-expression hotspots. mIF revealed extensive Trop2\u2013Nectin-4 protein colocalization across all tumors, whereas HER2 showed more restricted and heterogeneous expression. Triple-positive subpopulations were identified but were limited. Strikingly, all three markers exhibited pronounced tumor-specific upregulation relative to paired adjacent normal tissues, with surface plot analysis showing markedly elevated cumulative fluorescence intensities in tumors (Z-values approaching 240 arbitrary units) compared with a flattened landscape in normal tissues (Z-values &lt; 100\u2013120 arbitrary units). These findings provide a multi-scale description of ADC-target co-expression in bladder cancer and generate hypotheses for biomarker-driven patient stratification, which require validation in larger, independent cohorts.<\/jats:p>","DOI":"10.3390\/cimb48080825","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T11:33:46Z","timestamp":1786620826000},"page":"825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coordinated Expression of ADC Targets ERBB2, TACSTD2, and NECTIN4 in Bladder Cancer: A Multi-Scale Transcriptomic and Proteomic Landscape Analysis"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7682-053X","authenticated-orcid":false,"given":"Sanhe","family":"Liu","sequence":"first","affiliation":[{"name":"College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Department of Urology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China"},{"name":"Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Duan","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"},{"name":"Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaozhong","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Department of Urology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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