{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T16:59:35Z","timestamp":1785689975484,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Singapore Ministry of Health\u2019s National Medical Research Council","award":["TA21jun-0005"],"award-info":[{"award-number":["TA21jun-0005"]}]},{"name":"Singapore Ministry of Health\u2019s National Medical Research Council","award":["SEEDFD21jun-0002"],"award-info":[{"award-number":["SEEDFD21jun-0002"]}]},{"name":"Singapore Ministry of Health\u2019s National Medical Research Council","award":["CG21APR2002"],"award-info":[{"award-number":["CG21APR2002"]}]},{"name":"Singapore Ministry of Health\u2019s National Medical Research Council","award":["08\/FY2023\/EX\/27-A65"],"award-info":[{"award-number":["08\/FY2023\/EX\/27-A65"]}]},{"name":"RTF Seed Fund","award":["TA21jun-0005"],"award-info":[{"award-number":["TA21jun-0005"]}]},{"name":"RTF Seed Fund","award":["SEEDFD21jun-0002"],"award-info":[{"award-number":["SEEDFD21jun-0002"]}]},{"name":"RTF Seed Fund","award":["CG21APR2002"],"award-info":[{"award-number":["CG21APR2002"]}]},{"name":"RTF Seed Fund","award":["08\/FY2023\/EX\/27-A65"],"award-info":[{"award-number":["08\/FY2023\/EX\/27-A65"]}]},{"name":"TETRAD II Collaborative Centre Grant","award":["TA21jun-0005"],"award-info":[{"award-number":["TA21jun-0005"]}]},{"name":"TETRAD II Collaborative Centre Grant","award":["SEEDFD21jun-0002"],"award-info":[{"award-number":["SEEDFD21jun-0002"]}]},{"name":"TETRAD II Collaborative Centre Grant","award":["CG21APR2002"],"award-info":[{"award-number":["CG21APR2002"]}]},{"name":"TETRAD II Collaborative Centre Grant","award":["08\/FY2023\/EX\/27-A65"],"award-info":[{"award-number":["08\/FY2023\/EX\/27-A65"]}]},{"name":"SingHealth Duke-NUS AM\/ACP-Designated Philanthropic Fund","award":["TA21jun-0005"],"award-info":[{"award-number":["TA21jun-0005"]}]},{"name":"SingHealth Duke-NUS AM\/ACP-Designated Philanthropic Fund","award":["SEEDFD21jun-0002"],"award-info":[{"award-number":["SEEDFD21jun-0002"]}]},{"name":"SingHealth Duke-NUS AM\/ACP-Designated Philanthropic Fund","award":["CG21APR2002"],"award-info":[{"award-number":["CG21APR2002"]}]},{"name":"SingHealth Duke-NUS AM\/ACP-Designated Philanthropic Fund","award":["08\/FY2023\/EX\/27-A65"],"award-info":[{"award-number":["08\/FY2023\/EX\/27-A65"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including SPP1 (log2foldchange 3.49, adj. p = 0.0112), CXCL13, CD48, and CLEC5A, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher SPP1 expression (p = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between SPP1 protein and gene expression (r = 0.7016; p &lt; 0.00110), while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, SPP1 mRNA overexpression positively correlated with epithelioid histology (p = 0.007), higher tumor grade (p = 0.0023), non-head and neck location (p = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07\u20133.18, p = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, SPP1 overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of SPP1.<\/jats:p>","DOI":"10.3390\/ijms251910863","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T12:22:48Z","timestamp":1728476568000},"page":"10863","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High-Throughput Transcriptomics Identifies Chemoresistance-Associated Gene Expression Signatures in Human Angiosarcoma"],"prefix":"10.3390","volume":"25","author":[{"given":"Glenys Mai Shia","family":"Khor","sequence":"first","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"},{"name":"Raffles Institution, 1 Raffles Institution Ln, Singapore 575954, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Haghani","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany Rui En","family":"Tan","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth Chun Yong","family":"Lee","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6140-4824","authenticated-orcid":false,"given":"Bavani","family":"Kannan","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boon Yee","family":"Lim","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Yi","family":"Lee","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexi","family":"Guo","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1806-7370","authenticated-orcid":false,"given":"Tun Kiat","family":"Ko","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4801-3703","authenticated-orcid":false,"given":"Jason Yongsheng","family":"Chan","sequence":"additional","affiliation":[{"name":"Cancer Discovery Hub, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"},{"name":"Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore"},{"name":"Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S1470-2045(10)70023-1","article-title":"Angiosarcoma","volume":"11","author":"Young","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5833","DOI":"10.1172\/JCI139080","article-title":"Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma","volume":"130","author":"Chan","year":"2020","journal-title":"J. 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