DEVELOPMENT OF A NOVEL CANCER METASTASIS-ON-CHIP PLATFORM FOR DRUG DISCOVERY

Abstract

Metastasis is the cause of most triple-negative breast cancer deaths, yet anti-metastatic therapeutics remain limited. To develop new therapeutics to prevent metastasis, pathophysiologically relevant assays that recapitulate tumor microenvironment are essential for disease modeling and drug discovery. In this study, we have developed a new 3D microfluidic organ-on-chip model to mimic the early stages of cancer metastasis. This model integrates the triple-negative breast cancer cell line (MDA-MB-231), stromal fibroblasts, and a perfused microvessel. High-content imaging with automated quantification methods was optimized to assess the tumor cell invasion and intravasation within the model. Phenotypic screening of a targeted anti-cancer therapy drug library was conducted to evaluate the drug response sensitivity of our optimized model. We identified 30 compounds that reduced the tumor intravasation by 60% compared to controls. Multi-parametric phenotypic analysis was applied by combining the data from the metastasis-on-chip, cell proliferation, and 2D cell migration screens, revealing that the drug library was clustered into eight distinct groups with similar drug responses. Drugs with molecular targets: ABL, KIT, PDGF, SRC, and VEGFR were enriched in the drug clusters, showing a strong effect on tumor cell intravasation with less impact on cell invasion or cell proliferation, of which, Imatinib, a multi-kinase inhibitor targeting BCR-ABL/PDGFR/KIT. Further experimental analysis showed that Imatinib enhanced endothelial barrier stability as measured by trans-endothelial electrical resistance and significantly reduced the trans-endothelial invasion activity of tumor cells. Our findings demonstrate the potential of our novel metastasis-on-chip platform as a powerful tool for studying cancer metastasis biology, drug discovery aims, and assessing drug responses, offering prospects for personalized anti-metastatic therapies for triple-negative breast cancer patients.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences