Deep Visual Proteomics and spatial transcriptomics reveal the landscape of tumor malignancy in borderline ovarian cancer

ABSTRACT: Women of reproductive age can develop serous borderline tumors (SBT) characterized by the uncontrolled growth of epithelial cells that do not invade the stroma. Despite a good prognosis after surgery, SBT may recur as low-grade serous cancer (LGSC), which is invasive and responds poorly to current standard chemotherapy. SBT and LGSC have overlapping genomic changes, but a putative transition sequence is poorly understood. Here, we employ Deep Visual Proteomics (DVP), a recently introduced single cell type specific spatial technology, to elucidate the evolution of this cancer at the molecular level. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features (SBT-MP) which involves a gradual increase in MAPK signaling. Proteomics identified several neuronal proteins, including the splicing factor NOVA2, that are exclusive to LGSC and its corresponding metastasis. In the stroma we observed major differences between non-invasive and invasive phenotypes. An acute inflammatory response was only found in SBT-MP. Spatial transcriptomics complemented the insights gained from proteomics, showing an increase in c-Met signaling, mRNA splicing in the epithelium, and HIF1α/angiogenesis in stroma between SBT and the more invasive phenotypes. Inhibiting the most prominently regulated pathways validated our results and suggested an FDA-approved FOLR1 inhibitor as a potential therapeutic strategy. Knockdown or inhibition of the top hits identified using spatial proteomics and transcriptomics confirmed their functional significance regulating migration and invasion. Combining spatial proteomics with transcriptomics is a promising approach to gaining mechanistic insights into tumor transformations and identifying novel treatment strategies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Ovarian Low Malignant Potential Tumor Cell, Epithelial Cell, Stromal Cell, Ovary Cancer Cell

DISEASE(S): Ovarian Cancer

SUBMITTER: Mario Oroshi  

LAB HEAD: Matthias Mann

PROVIDER: PXD046354 | Pride | 2025-06-20

REPOSITORIES: Pride