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  3. Integration of cell-type resolved spatial proteomics and transcriptomics reveals novel mechanisms in early ovarian cancer

Integration of cell-type resolved spatial proteomics and transcriptomics reveals novel mechanisms in early ovarian cancer

  • medRxiv. 2025 Aug 28:2025.08.25.25333715. doi: 10.1101/2025.08.25.25333715.
Andreas Metousis 1,  Hilary A Kenny 2,  Aasa Shimizu 2,  Lisa Schweizer 1 2,  Shani Ben-Moshe 1,  Agnes Bilecz 2,  Rahul Krishnan 2,  Jingwen Zhang 2,  Isabel Alcazar 2,  Lucy Kelliher 2,  Mallika Ravi 2,  Tejas Samantaray 2,  Sabrina Richter 3,  Yan Li 4,  Jiying Wang 4,  Sophia Steigerwald 1,  Fabian J Theis 3,  Florian A Rosenberger 1 5,  Thierry M Nordmann 1,  S Diane Yamada 2,  Ricardo Lastra 6,  Matthias Mann 1,  Ernst Lengyel 2
Affiliations

Affiliations

  • 1 Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 2 Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL, USA.
  • 3 Institute of Computational Biology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany.
  • 4 Center for Research Informatics, The University of Chicago, Chicago, IL, USA.
  • 5 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
  • 6 Department of Pathology, The University of Chicago, Chicago, IL, USA.
PMID: 40909841 DOI: 10.1101/2025.08.25.25333715
Abstract

High-grade serous carcinoma (HGSC) is the most common ovarian Cancer subtype, typically diagnosed at late stages with poor prognosis. 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.

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