Microfluidic Microcirculation Mimetic for Exploring Biophysical Mechanisms of Chemotherapy-Induced Metastasis

Abstract

There is rapidly emerging evidence from pre-clinical studies, patient samples and patient subpopulations that certain chemotherapeutics inadvertently produce prometastatic effects. Prior to this, we showed that doxorubicin and daunorubicin stiffen cells before causing cell death, predisposing the cells to clogging and extravasation, the latter being a step in metastasis. Here, we investigate which other anti-cancer drugs might have similar prometastatic effects by altering the biophysical properties of cells. We treated myelogenous (K562) leukemic cancer cells with the drugs nocodazole and hydroxyurea and then measured their mechanical properties using a microfluidic microcirculation mimetic (MMM) device, which mimics aspects of blood circulation and enables the measurement of cell mechanical properties via transit times through the device. We also quantified the morphological properties of cells to explore biophysical mechanisms underlying the MMM results. Results from MMM measurements show that nocodazole- and hydroxyurea-treated K562 cells exhibit significantly altered transit times. Nocodazole caused a significant (p < 0.01) increase in transit times, implying a stiffening of cells. This work shows the feasibility of using an MMM to explore possible biophysical mechanisms that might contribute to chemotherapy-induced metastasis. Our work also suggests cell mechanics as a therapeutic target for much needed antimetastatic strategies in general.