Abstract
BackgroundBreast cancer is the most common invasive cancer among women. Currently, there are only a few models used for therapy selection, and they are often poor predictors of therapeutic response or take months to set up and assay. In this report, we introduce a microfluidic OrganoPlate® platform for extracellular matrix (ECM) embedded tumor culture under perfusion as an initial study designed to investigate the feasibility of adapting this technology for therapy selection.MethodsThe triple negative breast cancer cell lines MDA-MB-453, MDA-MB-231 and HCC1937 were selected based on their different BRCA1 and P53 status, and were seeded in the platform. We evaluate seeding densities, ECM composition (Matrigel®, BME2rgf, collagen I) and biomechanical (perfusion vs static) conditions. We then exposed the cells to a series of anti-cancer drugs (paclitaxel, olaparib, cisplatin) and compared their responses to those in 2D cultures. Finally, we generated cisplatin dose responses in 3D cultures of breast cancer cells derived from 2 PDX models.ResultsThe microfluidic platform allows the simultaneous culture of 96 perfused micro tissues, using limited amounts of material, enabling drug screening of patient-derived material. 3D cell culture viability is improved by constant perfusion of the medium. Furthermore, the drug response of these triple negative breast cancer cells was attenuated by culture in 3D and differed from that observed in 2D substrates.ConclusionsWe have investigated the use of a high-throughput organ-on-a-chip platform to select therapies. Our results have raised the possibility to use this technology in personalized medicine to support selection of appropriate drugs and to predict response to therapy in a real time fashion.
Highlights
Breast cancer is the most common invasive cancer among women
The three triple negative cell lines used in the experiments described subsequently were selected based on p53 and BRCA1 mutation status (Table 1), which allowed us to test sensitivity to relevant compounds which are reported to have differential responses when these genetic modifications are present
We employ a microfluidic organ-on-achip platform based on the standard 384-well plate format and we study its potential applicability for breast cancer therapy selection
Summary
Breast cancer is the most common invasive cancer among women. Currently, there are only a few models used for therapy selection, and they are often poor predictors of therapeutic response or take months to set up and assay. In the United States, over 200,000 new cases are diagnosed and about 40,000 women die from this disease each year [1, 2]. It is the most frequently diagnosed cancer among women globally and the leading cause of cancer death, with an estimated 1.7 million cases and 521,900 deaths in 2012 [3]. It can be sub-classified into ER+, PR+, HER2+ and triple negative breast cancer. The three triple negative cell lines used in the experiments described subsequently were selected based on p53 and BRCA1 mutation status (Table 1), which allowed us to test sensitivity to relevant compounds which are reported to have differential responses when these genetic modifications are present. We envision a possible screening strategy whereby cell cycle inhibiters and other standard chemotherapeutic agents such as, doxorubicin, and taxanes could be tested in vitro prior to therapy selection
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