Micromachines and motility: Single and collective cancer cell invasion

Cell migration and cell-matrix interactions regulate some of the most critical stages of tumor invasion and metastasis. However, our understanding of the systems level behavior of these processes is often plagued by culturing cells in artificial environments, focusing on a single protein or ignoring the interplay between cell-signaling and cellular mechanics. To understand the bi-directional interaction of cellular machinery and cell-signaling in single and collective cellular motion, we have developed an integrated experimental and computational approach combining mitochondria-tracking microrheology, microfluidics, and Brownian dynamics simulations. Our work analyzes, in both single cells and in cellular clusters that are up to a millimeter in diameter, in 2D and in 3D, both passive thermal and active motor-driven processes within the cell and demonstrate  how active internal fluctuations are modulated in native like environments. Our results demonstrate the synergistic roles of tension and signaling, dimensionality and disease progression and show that invasive cells  exhibit more solid-like internal motions in 3D compared to 2D. In addition, cells in 2D are more sensitive to actin disruption than in 3D. Our integrated approach has resulted in discovery of novel mechanisms of collective cellular motion, new regulators of cellular persistence in 3D environments and the role of ECM in modulating chemoresistance in breast and prostate cancer.