biostudies-literatureMakhmut AEuropean Research CouncilDeutschen Konsortium für Translationale Krebsforschung (DKTK)Berliner Krebsgesellschaft GrantBundesministerium für Bildung und Forschung (BMBF)7-41https://www.ebi.ac.uk/biostudies/studies/S-EPMC12759074biostudies-literatureUnknown22(1)High-grade serous ovarian cancer (HGSOC) is often detected at an advanced stage, where curative treatment options are limited. Recent advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover molecular drivers of early tumorigenesis and novel therapeutic targets. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, and concurrent invasive carcinoma, covering more than 10,000 proteins from ultra-low input archival tissue. STIC and HGSOC showed highly similar proteomes, clustering into two subtypes with distinct tumor-immune microenvironments and common remodeling of the extracellular matrix. We discovered cell-of-origin signatures from secretory fallopian tuMolecular systems biologySpatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets.PMC12759074DRFF202204101115681Young Investigator Grant 2022161L0222Dragomir MPFritzsche SSchmitt WDMoebs MMakhmut ATaube ETCoscia FfalseSpatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets.High-grade serous ovarian cancer (HGSOC) is often detected at an advanced stage, where curative treatment options are limited. Recent advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover molecular drivers of early tumorigenesis and novel therapeutic targets. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, and concurrent invasive carcinoma, covering more than 10,000 proteins from ultra-low input archival tissue. STIC and HGSOC showed highly similar proteomes, clustering into two subtypes with distinct tumor-immune microenvironments and common remodeling of the extracellular matrix. We discovered cell-of-origin signatures from secretory fallopian tu2026-01-01T00:00:00Z2026 Jan2026-07-15T11:18:59.763Z2026-07-04T03:11:32.781ZS-EPMC127590744123359510.1038/s44320-025-00168-4