High-throughput intracellular microrheology: a new tool for cancer research

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Summary Cancer mortality and morbidity are critically related to tumor invasion and metastasis in which the molecular mechanisms are poorly understood. Until their etiology is better revealed, attempts to develop new cancer therapeutics would remain empirical. Cell motility, which drives cancer metastasis, involves dynamic and regulated re-arrangements of the cytoskeleton. Our work and that of several other groups have shown that cytoskeleton phenotypes are typically accompanied by drastic changes in the viscoelastic properties of the cytoskeleton, which in turn modulate the ability of the cytoskeleton to generate net pushing forces at the leading edge and allow the cell to change its shape. Changes in cell mechanical properties have long been predicted to correlate with metastatic potential. However, current cell-mechanics approaches suffer from serious drawbacks - including time of measurement, lack of multiplexing, ambiguity of measurements - which prevent a direct test of this important hypothesis. The objective of this study is to: develop a highly-optimized high-throughput ballistic injection nanorheology (htBIN) technological platform to measure the micromechanical properties in cancer cells rapidly (< 30 s per cell) and reliably, and to assess these biophysical properties as a function of cell migration and invasion by comparing ovarian cancer cells of low and high invasive nature to normal cells, all obtained from patients at the Johns Hopkins Hospital. The proposed instrument, which is based on multiple-particle microrheology, presents key advantages over current approaches to cell mechanics. Our device will serve as a new tool for cancer research to study cell mechanics in the context of cancer cell migration and adhesion and may ultimately serve as a diagnostic tool for patients who are at high risk for ovarian cancer, complementing more conventional biomolecular markers of cancer in a clinical setting While our proposed approach to cell mechanics is a priori applicable to detect intracellular mechanical differences in any type of cancer cells, a primary focus of this project is ovarian cancer. Ovarian cancer was selected as the disease model in this study because it represents one of the most aggressive cancers in women.