An omentum-inspired 3D PEG hydrogel for identifying ECM-drivers of drug resistant ovarian cancer

Abstract

Ovarian cancer (OvCa) is a challenging disease to treat due to poor screening techniques and late diagnosis. There is an urgent need for additional therapy options, as patients recur in 70% of cases. The limited availability of clinical treatment options could be a result of poor predictions in early stage drug screens on standard tissue culture polystyrene (TCPS). TCPS does not capture the mechanical and biochemical cues that cells experience <i>in vivo</i>, which can impact how cells will respond to a drug. Therefore, an <i>in vitro</i> model that captures some of the microenvironment features that the cells experience <i>in vivo</i> could provide better insights into drug responses. In this study, we formed 3D multicellular tumor spheroids (MCTS) in microwells and encapsulated them in 3D omentum-inspired hydrogels. SKOV-3 MCTS were resistant to Paclitaxel in our 3D hydrogels compared to a monolayer on TCPS. Toward clinical application, we tested cells from patients [ovarian carcinoma ascites spheroids (OCAS)] who had been treated with Paclitaxel, and drug responses predicted by using the 3D omentum-inspired hydrogels demonstrated the lack of the Paclitaxel response of these samples. Additionally, we observed the presence of collagen production around the encapsulated SKOV-3 MCTS, but not significantly on TCPS. Our results demonstrated that our 3D omentum-inspired hydrogel is an improved <i>in vitro</i> drug testing platform to study the OvCa drug response for patient-derived cells and helped us identify collagen 3 as a potential driver of Paclitaxel resistance in 3D.