<b>Abstract</b><br/>Cancer cell chemotaxis induced by spatial gradients of chemokines and growth factors plays an essential role in cancer progression and metastasis. Recent studies reveal that solid tumors consist of heterogeneous types of cells with distinct phenotypes and functions. However, it is unclear how different subtypes of cancer cells behave in chemotaxis induced by multiple gradients. In this work, we have developed a microfluidic device for the generation of multiple gradients and studied chemotaxis of cancer stem cells and cancer cells at the single-cell level. The microfluidic network enabled generation of multiple continuous linear gradients, entrapment and growth of cancer cells, and real-time monitoring of cellular behaviors. The gradient-dependent migratory ability of lung cancer stem cell (LCSC) and differentiated LCSC (dLCSC) was investigated in the presence of multiple serum gradients. Cancer cells elongated in the direction of gradient and migrated faster in the higher gradient, and such behavior was attenuated by the inhibition of β-catenin signaling in both LCSC and dLCSC. Interestingly, we have observed the acceleration of LCSC and dLCSC during chemotaxis in multiple gradients, which has also been verified by the cell biosenser model that predicted the chemotactic acceleration tendency. Our results also demonstrated that LCSC was less sensitive response to the serum gradient stimulation showing a slower migration rate, compared to dLCSC, consistent with the down-regulation of migration-related genes, such as EGFR and WNT3a, in LCSC. These findings implicated that individual cancer stem cells and cancer cells from the same origin behaved differently in the response to the same external stimuli, suggesting the importance of cancer cell heterogeneity in tumor procession and metastasis. The microfluidic device provides a novel platform for the study of cell heterogeneity in chemotaxis in the complex microenvironment.

Gradient-induced migration of cancer stem cells in a microfluidic network revealed chemotactic acceleration and the involvement of Wnt/β-catenin pathway

249th National Meeting (2015)

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