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Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression

ABSTRACT: Epithelial serous borderline tumors (SBT) are non-invasive neoplastic ovarian lesions that may recur as chemo-resistant low-grade serous cancer (LGSC). While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood. Here, we integrate cell-type resolved spatial proteomics and transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastasis in both the stroma and the tumor. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features. LGSC overexpressed the c-Met receptor tyrosine kinase and several CNS-specific proteins. In the tumor microenvironment, interconnectivity between cancer and tumor cells and enzymes degrading a packed extracellular matrix suggests functional collaboration between various cells in the tumor organ. Integrating spatial transcriptomics and proteomics, we functionally validate 16 drug targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289044 | GEO | 2025/06/25

REPOSITORIES: GEO

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Project description: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.

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Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression.

Project description:Serous borderline tumors (SBT) are epithelial neoplastic lesions of the ovaries that commonly have a good prognosis. In 10-15% of cases, however, SBT will recur as low-grade serous cancer (LGSC), which is deeply invasive and responds poorly to current standard chemotherapy1,2,3. While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood4. Here, we integrate spatial proteomics5 with spatial transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastasis at the molecular level in both the stroma and the tumor. 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. A distinct subset of proteins and transcripts was associated with the transition to invasive tumor growth, including the neuronal splicing factor NOVA2, which was limited to expression in LGSC and its corresponding metastasis. An integrative pathway analysis exposed aberrant molecular signaling of tumor cells supported by alterations in angiogenesis and inflammation in the tumor microenvironment. Integration of spatial transcriptomics and proteomics followed by knockdown of the most altered genes or pharmaceutical inhibition of the most relevant targets confirmed their functional significance in regulating key features of invasiveness. Combining cell-type resolved spatial proteomics and transcriptomics allowed us to elucidate the sequence of tumorigenesis from SBT to LGSC. The approach presented here is a blueprint to systematically elucidate mechanisms of tumorigenesis and find novel treatment strategies.

| S-EPMC10680885 | biostudies-literature

The DNA methylomes of serous borderline tumours reveal subgroups with malignant-like or benign-like profiles

Project description:Serous borderline tumours (SBOT) are a challenging group of ovarian tumours positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low grade serous carcinoma (LGSC), 19 SBOT and 16 benign serous tumours (BST) across 27,578 CpG sites to further characterise the epigenomic relationship between these subtypes of ovarian tumours. Unsupervised hierarchical clustering of DNA methylation levels showed that LGSC differ distinctly from BST, however, not from SBOT. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSC and BST revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signalling and the extracellular region consistent with a more invasive phenotype of LGSC as compared to BST. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant-like or benign-like methylation profiles. Furthermore, a two loci DNA methylation signature can distinguish between these SBOT subgroups with benign-like and malignant-like methylation characteristics. Our findings indicate striking similarities between SBOT and LGSC methylomes which supports a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOT can be classified into tumours with a benign-like or a malignant-like methylation profile which may help in identifying tumours more likely to progress into LGSC. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in 12 low grade serous carcinoma, 19 serous borderline tumours and 16 benign serous tumours. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using four biological replicates of the high grade serous ovarian cancer cell line PEO1. Differential methylation cutoff was estimated from four biological replicates by bootstrap resampling and set at Δβ ≥ 0.25 corresponding to a FDR ≤ 0.09.

2012-12-31 | E-GEOD-40105 | biostudies-arrayexpress

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