{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T04:15:16Z","timestamp":1761192916769,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>High-grade serous carcinoma (HGSC) of the ovary is characterized by two major histological patterns: a classic papillary\/micropapillary architecture and a solid pseudo-endometrioid transitional (SET) variant. We investigated whether the distinct morphologic subtypes are underpinned by transcriptomic differences in the tumor microenvironment (TME). We profiled 21 HGSC tumors (7 SET, 14 classic) using a 770-gene NanoString PanCancer Progression panel. Differential expression analysis revealed ~20 genes with significantly different expression (&gt;4-fold, adjusted p &lt; 0.01) between SET and classic tumors. Unsupervised clustering partially separated SET and classic tumors, suggesting that global gene expression patterns correlate with histologic subtype. SET tumors exhibited upregulation of cell-cycle and epithelial genes (e.g., PTTG1, TRAIL, HER3) and downregulation of genes involved in epithelial\u2013mesenchymal transition (EMT), extracellular matrix (ECM) organization, and angiogenesis (e.g., TWIST2, FGF2, decorin) relative to classic tumors. Notably, PTTG1 and TRAIL were upregulated ~6\u20139-fold in SET tumors, whereas TWIST2 was ~7-fold downregulated, consistent with reduced EMT in SET tumors. Pathway analysis indicated that SET tumors appear to have an immune-active, stroma-poor microenvironment, in line with an \u201cimmunoreactive\u201d phenotype, whereas classic tumors showed a mesenchymal, stroma-rich profile. These molecular distinctions could have diagnostic utility and may inform therapeutic stratification, with key dysregulated genes (e.g., HER3, TRAIL, FGF2) representing potential prognostic or predictive biomarkers. For example, high HER3 expression in SET tumors might predict sensitivity to ERBB3\/PI3K inhibitors, whereas stromal factors (e.g., FGF2) enriched in classic HGSC could be targeted with microenvironment-modulating therapies. These preliminary findings require validation before translation into pathology practice via immunohistochemical (IHC) assays (e.g., for HER3 or TRAIL), potentially enabling improved classification and personalized treatment of HGSC. We report effect sizes as log2 fold change with 95% confidence intervals and emphasize FDR-adjusted q-values. Given the small sample size and the absence of outcome data (OS\/PFS\/PFI), results are preliminary and hypothesis-generating. Orthogonal protein-level validation and replication in larger, independent cohorts are required before any translational inference.<\/jats:p>","DOI":"10.3390\/ijms262010229","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:42:03Z","timestamp":1761054123000},"page":"10229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Profiling of the Tumor Microenvironment in High-Grade Serous Carcinoma: A Pilot Study of Morphologic and Molecular Distinctions Between Classic and SET Patterns"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-0219","authenticated-orcid":false,"given":"Riccardo","family":"Giannini","sequence":"first","affiliation":[{"name":"Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell\u2019Area Critica, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2702-3259","authenticated-orcid":false,"given":"Francesco","family":"Bartoli","sequence":"additional","affiliation":[{"name":"Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katia De","family":"Ieso","sequence":"additional","affiliation":[{"name":"D.A.I. Oncologia, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiziano","family":"Camacci","sequence":"additional","affiliation":[{"name":"D.A.I. Oncologia, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6322-9799","authenticated-orcid":false,"given":"Andrea","family":"Bertolucci","sequence":"additional","affiliation":[{"name":"D.A.I. Chirurgia Generale e Urologia, U.O. Chirurgia Generale e Peritoneale SSN, Centro Clinico Chirurgia del Peritoneo SSN, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Piccini","sequence":"additional","affiliation":[{"name":"D.A.I. Chirurgia Generale e Urologia, U.O. Chirurgia Generale e Peritoneale SSN, Centro Clinico Chirurgia del Peritoneo SSN, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erion","family":"Rreka","sequence":"additional","affiliation":[{"name":"D.A.I. Chirurgia Generale e Urologia, U.O. Chirurgia Generale e Peritoneale SSN, Centro Clinico Chirurgia del Peritoneo SSN, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duccio","family":"Volterrani","sequence":"additional","affiliation":[{"name":"Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Gemignani","sequence":"additional","affiliation":[{"name":"Dipartimento di Biologia, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-6357","authenticated-orcid":false,"given":"Stefano","family":"Landi","sequence":"additional","affiliation":[{"name":"Dipartimento di Biologia, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Ugolini","sequence":"additional","affiliation":[{"name":"Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell\u2019Area Critica, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7424-4335","authenticated-orcid":false,"given":"Piero Vincenzo","family":"Lippolis","sequence":"additional","affiliation":[{"name":"D.A.I. Chirurgia Generale e Urologia, U.O. Chirurgia Generale e Peritoneale SSN, Centro Clinico Chirurgia del Peritoneo SSN, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-1083","authenticated-orcid":false,"given":"Pinuccia","family":"Faviana","sequence":"additional","affiliation":[{"name":"Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell\u2019Area Critica, Universit\u00e0 di Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/nature10166","article-title":"Integrated Genomic Analyses of Ovarian Carcinoma","volume":"474","author":"Bell","year":"2011","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1097\/PGP.0b013e31824c2372","article-title":"Architectural Patterns of Ovarian\/Pelvic High-Grade Serous Carcinoma","volume":"31","author":"Bromley","year":"2012","journal-title":"Int. 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