Introduction

Ovarian High-Grade Serous Carcinoma (HGSOC) is the most common ovarian carcinoma and is an aggressive disease that is frequently detected at advanced stages. Median 5-year survival rates are between 15% and 55%, with stage and degree of debulking being the major prognostic factors. Despite high initial responses to chemotherapy in about 65% of patients, most cases recur. Early detection and prognosis are urgently needed; this is where Mass spectrometry-based proteomics plays a key role in biomarker detection.

Methods

Treatment-naïve, formalin-fixed paraffin-embedded (FFPE) tissues from 77 HGSOC patients were measured via liquid-chromatography mass-spectrometry (LC-MS/MS) based proteomics in data independent acquisition mode (DIA). Results

We identified more than 4000 proteins per sample, 3500 of which with less than 20% missing values. In a hierarchical clustering analysis, we could highlight distinct proteomic differences between three interconnected clusters:

Cluster 1: Upregulation of proteins linked to innate immunity and extracellular matrix (ECM) organization, with reduced metabolic activity.

Cluster 2: High aerobic respiration and antigen processing/presentation, with decreased cell motility.

Cluster 3: Lower immune infiltration and upregulated organic acid synthesis.

We found that immune cell markers were enriched in Cluster 1, as were extracellular matrix proteins. Conversely, epigenetic regulators were increased in Cluster 2, suggesting increased genomic plasticity. We also detected antibody-drug conjugate (ADC) targets, such as FOLR1 and MSLN with differential abundance.

Conclusion

Our proteomic analysis revealed three interconnected clusters within the cohort, reflecting continuous variations rather than separate biological entities. These findings highlight the complex proteomic landscape of HGSOC and identify potential biomarkers and therapeutic targets.