Collective amoeboid dynamics drives colonization of drug-resistant ovarian cancer cells

Abstract

Epithelial ovarian cancer (EOC) is characterized by resistance to platinum-based therapy, resulting in rapid progression and poor survival. Here, we ask whether drug resistance and invasiveness coevolve to drive metastasis. Selection experiments involving pulsed carboplatin exposure established isogenic chemoresistant variants of lines, which typify high-grade serous ovarian carcinoma (HGSOC), the most aggressive type of EOC. Time-lapse imaging showed enhanced migration of resistant single cells and their collectives. Resistant cell spheroids spread faster on Collagen I substrata than sensitive controls. The resistant OVCAR-3 transcriptome was ontologically enriched for migration and showed overlap with previously reported markers of resistance in EOC patients and other evolved lines. Gene set enrichment predicted transition between epithelial, mesenchymal, and amoeboid states is higher in resistance compared to control lines. Lower matrix adhesion, weak focal adhesion, and highly deformable and translatory dynamics of cell collectives indicated that resistant cancer cells displayed a unique collective amoeboid-like migration. When injected intraperitoneally into immunodeficient mice, resistant cells colonized to a greater extent on parietal mucosae. Ex vivo, suspended resistant cells formed moruloids associated with quicker peritoneal adhesion, clearing human coelomic mesothelial monolayers with higher efficiency. Knockdown in resistant OVCAR-3 cells of two upregulated proteins, E-cadherin and LGALS3BP, had distinct consequences. E-cadherin knockdown partially restored sensitivity to carboplatin but did not affect invasion. In contrast, silencing LGALS3BP decreased invasion but not resistance. Our results suggest that drug resistance and invasiveness could coevolve through the upregulation of distinct trait drivers in EOC.