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

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.