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  3. Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets

Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets

  • Mol Syst Biol. 2025 Nov 13. doi: 10.1038/s44320-025-00168-4.
Anuar Makhmut # 1 2,  Mihnea P Dragomir # 3 4 5,  Sonja Fritzsche 1 6,  Markus Moebs 3,  Wolfgang D Schmitt 3,  Eliane T Taube 3 7,  Fabian Coscia 8
Affiliations

Affiliations

  • 1 Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Spatial Proteomics Group, Berlin, Germany.
  • 2 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany.
  • 3 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany.
  • 4 Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 5 German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 6 Humboldt-Universität zu Berlin, Institute of Biology, Berlin, Germany.
  • 7 Institute of Pathology, Diagnostik Ernst von Bermann, Potsdam, Germany.
  • 8 Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Spatial Proteomics Group, Berlin, Germany. [email protected].
  • # Contributed equally.
PMID: 41233595 DOI: 10.1038/s44320-025-00168-4
Abstract

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 tube epithelial cells in STICs and identified early dysregulated pathways of therapeutic relevance. Targeting Cholesterol biosynthesis by inhibiting the terminal steps via DHCR7 showed therapeutic effects in ovarian Cancer cell lines and synergized with standard-of-care carboplatin treatment. This study demonstrates the power of spatially resolved quantitative proteomics in understanding early carcinogenesis and provides a rich resource for biomarker and drug target research.

Keywords

Cancer Proteomics; High-Grade Serous Ovarian Cancer; Serous Tubal Intraepithelial Carcinoma; Spatial Tissue Proteomics.

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