Proteomic Landscapes of 3D and 2D Models of High-Grade Serous Ovarian Carcinoma: Implications for Carboplatin Response

High-grade serous ovarian carcinoma (HGSOC) is the most
common
form of ovarian cancer, and finding new treatments remains an unmet
need. While drug discovery is typically performed in two-dimensional
(2D) monolayers, three-dimensional (3D) culture systems better mimic
the in vivo conditions. However, a comprehensive comparison of 3D
versus 2D ovarian cancer models is lacking. Here, we quantitatively
compared the whole cell proteomic signatures of four ovarian cell
linesPEO1, PEO4, UWB1.289, and UWB1.289+BRCA1with
different status of BRCA genes grown in 2D and 3D. Using isobaric
labeling proteomics, we quantified 6404 proteins and identified 371
significantly and commonly altered proteins between 2D and 3D. Proteins
upregulated in 3D were enriched for transmembrane transport and NADH:ubiquinone
oxidoreductase complex I, while energy metabolism and cell growth
pathways also showed dimensionality-dependent changes. Notably, membrane-associated
proteins were downregulated in spheroids, particularly EGFR in PEO1.
Furthermore, the 3D culture modulated the response to carboplatin,
with an increased expression of drug resistance-associated proteins,
including NDUF family members in all spheroid models. These findings
underscore how culture dimensionality influences both the molecular
landscape and the chemotherapeutic response of HGSOC cells and highlights
candidate targets for overcoming carboplatin resistance.