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

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 remodelling 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Oviduct

SUBMITTER: Fabian Coscia

LAB HEAD: Dr. Fabian Coscia

PROVIDER: PXD069630 | Pride | 2025-10-19

REPOSITORIES: Pride

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			Action	DRS
	DIANN_search_results_STIC_figure3F.rar	Other
	DIANN_search_results_predicted_library.rar	Other
	ProtContLib.fasta	Fasta
	Raw_data_Fig3F.rar	Other
	Raw_data_cohort__part2.rar	Other

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