Fibroblast-derived gremlin-1 Is associated with ovarian cancer-cell phenotypes in co-culture models.

BACKGROUND

Cancer-associated fibroblasts (CAFs) can modify ovarian cancer-cell behavior through paracrine signals, but the contribution of CAF-derived Gremlin-1 remains incompletely defined.

METHODS

We compared stage IV and stage I ovarian-cancer transcriptomes in GSE9891, performed functional-enrichment analyses of differentially expressed genes, and interrogated CSIOVDB and KM Plotter for GREM1 expression patterns, clinicopathologic associations, EMT-score correlation, and survival outcomes. We also measured GREM1 mRNA in a small cohort of normal, benign and malignant ovarian tissues. In vitro, SKOV3 and A2780 cells were exposed to rGremlin-1, and GREM1 expression was manipulated by overexpression or knockdown in commercial fibroblasts marketed as CAFs (hereafter 'CAFs') under co-culture conditions. Cell viability, invasion, migration, apoptosis, EMT markers and, in SKOV3 cells, FGFR1/MEK/ERK phosphorylation were assessed.

RESULTS

GSE9891 DEGs were enriched in ECM-related processes. CSIOVDB associated higher GREM1 expression with tumor stroma, peritoneal metastasis, advanced stage, higher grade, a mesenchymal subtype, and EMT score. In a small exploratory tissue cohort, GREM1 expression showed a numerical increase in benign and malignant ovarian tumors relative to normal tissue, consistent in direction with the CSIOVDB findings, but this pattern was not statistically significant and should be interpreted as descriptive rather than confirmatory. rGremlin-1 exposure altered invasion, migration, EMT markers, and apoptosis, while the SKOV3 CCK-8 response was biphasic. CAF GREM1 gain- and loss-of-function produced opposing changes in several co-culture phenotypes, although some responses were cell-line or time dependent. In SKOV3 cells, OE GREM1 CAFs were associated with higher p-FGFR1/FGFR1, p-MEK1/2/MEK1/2 and p-ERK1/2/ERK1/2 ratios; shGREM1 reduced the p-ERK1/2/ERK1/2 ratio, whereas the p-FGFR1/FGFR1 and p-MEK1/2/MEK1/2 contrasts were not significant.

CONCLUSION

CAF GREM1 expression was associated with selected phenotypes in SKOV3 and A2780 cells under the tested in vitro conditions. FGFR1/MEK/ERK phosphorylation patterns in SKOV3 cells suggested a candidate signaling link. Further validation in independently characterized CAF models and additional ovarian-cancer systems is needed.