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Understanding early molecular events driving HGSC progression is crucial for timely detection and development of effective treatment strategies. We performed and integrated spatial cell-type resolved proteomics and paired transcriptomics across 25 women with precursor lesions of the fallopian tube and\/or HGSC. Epithelial cell signatures revealed early activation of SUMOylation machinery, increased ATR and Wnt signaling, and enhanced MHC-I antigen presentation along the disease trajectory. The stroma exhibited extracellular matrix remodeling and interferon-mediated inflammation. Serous tubal intraepithelial carcinomas (STICs) in cancer patients contained a pro-coagulative signature and reduced APOA1\/2 compared to STICs in individuals without cancer. We functionally established important roles of epithelial-derived TRIP13 and SUMOylation, and cancer-associated fibroblast-derived SULF1 and BGN in HGSC progression. These findings provide unique molecular insights into HGSC pathogenesis and identify potential new therapeutic targets for intervention.<\/jats:p>","DOI":"10.1101\/2025.08.25.25333715","type":"posted-content","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:15:26Z","timestamp":1756426526000},"source":"Crossref","is-referenced-by-count":2,"title":["Integration of cell-type resolved spatial proteomics and transcriptomics reveals novel mechanisms in early ovarian cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1043-6591","authenticated-orcid":false,"given":"Andreas","family":"Metousis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2396-967X","authenticated-orcid":false,"given":"Hilary A.","family":"Kenny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2631-3182","authenticated-orcid":false,"given":"Aasa","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1165-7804","authenticated-orcid":false,"given":"Lisa","family":"Schweizer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7046-5423","authenticated-orcid":false,"given":"Shani","family":"Ben-Moshe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5231-2669","authenticated-orcid":false,"given":"Agnes","family":"Bilecz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8673-515X","authenticated-orcid":false,"given":"Isabel","family":"Alcazar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6943-4321","authenticated-orcid":false,"given":"Lucy","family":"Kelliher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mallika","family":"Ravi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4442-2207","authenticated-orcid":false,"given":"Tejas","family":"Samantaray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Richter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-1131","authenticated-orcid":false,"given":"Sophia","family":"Steigerwald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2419-1943","authenticated-orcid":false,"given":"Fabian J.","family":"Theis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4604-6170","authenticated-orcid":false,"given":"Florian A.","family":"Rosenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3702-815X","authenticated-orcid":false,"given":"Thierry M.","family":"Nordmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. 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