Fibronectin and E-cadherin regulate unique invasive traits of drug-resistant ovarian cancer cells

Rapid progression in epithelial ovarian cancer (EOC) is characterized by resistance to platinum-based therapy. We asked if the kinetics of progression is regulated by coevolution of cancer cell invasiveness with drug resistance. Isogenic carboplatin-resistant counterparts of human high-grade serous ovarian cancer cells were observed to invade better through, and on, extracellular matrix (ECM) and within murine peritonea. The resistant cell transcriptome was ontologically enriched for signatures of migration, confirmed previously reported resistance signatures in patients, and revealed elevation of both fibronectin and E-cadherin: markers of mesenchymal and epithelial traits. Higher translatory and deformable dynamics of resistant cell collectives and their greater ability to clear surrounding mesothelia indicated that resistant cells also displayed better collective migration. E-cadherin knockdown partially restored sensitivity to carboplatin and decreased collective integrity but did not affect cell migration. In contrast, silencing fibronectin decreased single-cell migration but did not affect resistance and integrity. Therefore, unique migratory abilities coevolve with EOC drug resistance by upregulating distinct regulators of cellular traits.