Category: Assay Development and Screening

1060-A - High Throughput Three-Dimensional Micro-tumor Array for Efficient in vitro Drug Screening

Monday, February 5, 2018
2:00 PM - 3:00 PM

Poor understanding and recapitulation of complex human biology during in vitro drug screening has contributed to high failure rates of modern drug discovery and development. Extracellular matrix (ECM) and stromal cells have been identified to be vital components of tumor microenvironments and crucially influence anti-tumor treatment efficacy. Biomimetic three-dimensional (3D) models have gained much attention in attempt to better evaluate potential therapies, however protocols for such models can be complicated. We have developed a versatile, miniaturized and ready-to-use microscaffold array to simplify 3D culture. Using basic cell culture techniques, biomimetic 3D micro-tumors could be generated in 384-well plate format for high throughput anti-cancer therapeutic screening. A range of cell lines has been tested on our array with reproducible proliferation and cell viability. Our microtissue array demonstrated high assay quality and robustness as indicated by Z’-factor (>0.5), coefficient of variance (<0.15) and dose-response curves. By generating 3D microtissues of tumor cell lines, we have found increased resistance of these cell lines towards chemotherapeutics and targeted drugs, in comparison to two-dimensional (2D) culture. Not only so, cell-line generated or primary cell-generated micro-tumor arrays are able to identify novel small molecule compounds or clinical drug combinations that could effectively inhibit tumor growth in cell-line derived xenograft or patient-derived xenograft models respectively. To augment mimicry of in vivo microenvironment, stromal barriers have also been recreated by including activated fibroblasts during micro-tumor generation. Decreased anti-tumor effects of chemotherapeutics and immune cell therapy (CAR-T) are observed as the stromal barriers impeded penetration of these agents. Screening of chemotherapeutic agents in combination with vitamin D receptor ligand to reprogram stromal cells on our microtissue array has shown improved anti-tumor effects, which is verified in xenograft models. In conclusion, our ready-to-use microscaffold array provides a powerful tool to generate 3D in vitro models in an easy-to-use manner. We anticipate it will bridge the gap between 2D monolayer culture and in vivo models to provide early efficacy and safety insights into potential therapeutic candidates, hence reducing developmental costs and high attrition rates, ultimately accelerating therapeutic discovery.

Xiaojun Yan

Ph.D. Student
Tsinghua University School of Medicine
Beijing, Beijing, China (People's Republic)

Xiaojun Yan (Ph.D. Candidate, Tsinghua University)
2015-2018: Doctoral in Philosophy (PhD) in Biomedical Engineering
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China
2012-2015: Master’s in Biomedical Engineering
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China
2008-2012: Bachelors in Engineering
Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore