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Fibronectin and E-cadherin drive collective invasion in drug-resistant ovarian cancer cells

ABSTRACT: Rapid progression in epithelial ovarian cancer (EOC) is characterized by resistance to platinum-based therapy. We asked if progression kinetics is caused by coevolution of invasiveness with drug resistance. Isogenic carboplatin-resistant counterparts of high grade serous human cancer cells invaded better through, and on, ECM and within murine peritonea. The resistant cell transcriptome was ontologically enriched for signatures of migration, erstwhile reported resistance signatures in patients and mediators of transition between epithelial, mesenchymal, and amoeboid states, which was confirmed through higher expression of fibronectin and E-cadherin. Lower matrix adhesion, weak focal adhesion, and higher translatory dynamics of deformable cell collectives that could clear surrounding mesothelia indicated that resistant cancer cells displayed a unique collective amoeboid-like migration. E-cadherin knockdown partially restored sensitivity to carboplatin and decreased collective integrity, but did not affect migration. In contrast, silencing fibronectin decreased migration but did not affect resistance and integrity. Therefore, unique migrative abilities coevolve with EOC drug-resistance through the upregulation of distinct molecular trait drivers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285737 | GEO | 2025/01/07

REPOSITORIES: GEO

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Project description:Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies. It is well established that cancer invasion and metastasis still represent the major causes of the failure of cancer treatment. Previously, we identified the mannose receptor LY75 (DEC205/CD205) gene as notably hypomethylated in high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. LY75 has been identified as a putative antigen-uptake receptor, which is expressed abundantly on dendritic cells, which are specialist antigen presenting cells to T lymphocytes for the initiation of an immune response. The implication of LY75 in EOC tumorigenesis is currently unknown. Here we show that LY75 is strongly overexpressed in HG serous EOC tumors as compared to normal ovarian tissue. Importantly, shRNA-mediated LY75 knockout in the mesenchymal EOC cells (SKOV3) led to mesenchymal to epithelial transition (MET), associated with overexpression of epithelial markers E-cadherin and EPCAM and loss of expression of mesenchymal markers Fibronectin, N-cadherin Snail1 and Twist1. In addition, LY75 suppression significantly inhibited EOC cell migration and invasion in vitro. However, LY75 knockdown led to enhanced tumor cell dissemination and significantly increased lethality in vivo, in xenograft model of advanced peritoneal EOC. Thus, our findings indicate that LY75 could play an essential role in the mesenchymal-to-epithelial transition (MET) of EOC cells and support the hypothesis that, while epithelial-to-mesenchymal transition (EMT) enables the invasiveness of tumor cells, a MET-associated epithelial phenotype could be essential for their metastatic colonization. To better understand the molecular mechanisms of LY75 gene action in epithelial ovarian cancer (EOC), we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon LY75 suppression in SKOV3 EOC cells. We compared the gene expression of the previously selected shRNA-mediated LY75-knockdown clones sh-S3 and sh-S6 against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for each of the LY75-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

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Fibronectin and E-cadherin drive collective invasion in drug-resistant ovarian cancer cells

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