An Automatable Hydrogel Culture Platform for Evaluating Efficacy of Antibody‐Based Therapeutics in Overcoming Chemoresistance. Issue 5 (24th February 2020) - Kletzmayr, Anna
Abstract: The microenvironment plays a major role in conferring chemoresistance to cancer cells. In order to better inform clinical response to chemoresistance, preclinical models that recapitulate its hallmark features are needed to enable screening for resistance‐specific therapeutic targets. A novel platform for seeding cancer cells in 3D hydrogels is presented utilizing derivatives of chitosan and alginate that, critically, is amenable to high throughput screening: cell seeding in hydrogels, media changes, dosing of anticancer compounds, and cell viability assays are all automated using a standard and commercially available liquid handling robot. Culture in these hydrogels elicits resistance in ovarian, lung, and prostate cancer cells to treatment by doxorubicin and paclitaxel. In correlation, proteomics analysis of SKOV3 cells cultured in 3D reveals enrichment of proteins associated with extreme drug resistance including HMOX1 and ALDH2. Subsequently, therapeutic antibodies targeted to tumor‐associated antigens upregulated in 3D cultures are shown to have higher efficacy compared to 2D cultures. Collectively, this automated 3D cell culture platform provides a powerful tool with utility in identification of drugs that may overcome chemoresistance. Abstract : A standard liquid handling robot is used to rapidly seed cancer cells in hydrogels comprising chemically defined polysaccharides at room temperature and without the need for enzymes or other polymerization catalysts. Cancer cells cultured this way exhibit enriched expression of tumor‐associated antigens. This work offers drug developers an automatable 3D culture system for higher throughput screening, particularly for antibody therapeutics.