Development of Microfluidic Techniques for Quantitative Study of Cancer Cell Migration under Bio/Chemical Stimulation and Mechanical Stress


Student thesis: Doctoral Thesis

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Award date25 Apr 2017


More than 90% of cancer deaths are the result of tumor metastasis. However, due to the lack of understanding of the metastatic cascade, which is an extreme dynamic and complex process, there are limited therapeutic approaches that can effectively prevent or interrupt cancer metastasis. The study of the intricate interactions within the tumor microenvironment will provide critical information towards the eventual understanding and inhibition of cancer metastases.

Recently, the development of microfluidics techniques serves as a promising and emerging tool in understanding cancer biology and in cancer diagnosis. Developing and applying the state of the art microfluidic technologies to address the unmet challenges in cancer can expand the horizons of not only fundamental biology but also the management of disease and patient care. In this thesis, we designed and fabricated a suite of microfluidics tools with biomimetic tumor microenvironment to investigate the mechanisms that govern cancer metastasis focusing on understanding how chemical and mechanical cues in tumor microenvironment regulate cell migration and transition during metastasis.

(1) A V-shape microfluidic device capable of generating multiple stable concentration gradients for the cancer cells chemotaxis process study was designed and fabricated showing the dynamic and differential response of both LCSC and dLCSC to chemotaxis, especially for the first time, the acceleration of cancer cells during chemotaxis caused by increasing local concentration in different gradients, suggesting the importance of cancer cell heterogeneity.

(2) A microfluidic narrow channel array to mimic the physical pressure during cancer metastasis was designed and fabricated for real-time monitoring on cancer cell migration. This work showed that physical confinement regulates cancer cell EMT state and the cells with mesenchymal transition appeared to be more elastic with greater motility than the epithelial phenotype.

(3) Leader cancer cells in 2D and 3D cancer cell migration assay was analyzed. This work showed the evidences that cancer leader cells at the tips of the collective cell migration fingers, which can be enhanced by physical stress, showed EMT-related genes upregulated and especially snail family genes upregulated at single cell level indicating the potential gene target for inhibiting cancer metastasis.

(4) A microfluidic device for capturing and isolating CTCs by the physical dimensions was designed and fabricated by the physical dimensions. Additionally, we developed a simple liquid PDMS infusion method to generate a surface with slippery and anti-fouling property enabling better whole blood manipulation with high capturing efficiency and high sensitivity for the cancer cell isolation.

The series of microfluidic devices providing tumor-mimicking microenvironments for cancer metastasis study which ultimately could be applied as a point-of-care diagnostic device for targeted cancer metastasis diagnosis.