Migrations of metastatic cells throughout the human body can seed secondary cancers at various locations, often with deadly consequences to the patient. Decades of intense research have established that metastatic cancer cells differ from the non-metastatic ones in terms of their genetics, molecular composition, and their increased motility. Despite these advances, there are currently no approved drugs available that target motility of metastatic cancer cells. This is in large part due to our limited understanding of what processes underlie the increased motility of the metastatic cells. We have recently shown that non-metastatic and metastatic cells migrate in fundamentally different ways. While non-metastatic cells execute simple, diffusive random walks, their metastatic variants in all experimental systems (1D microtracks, 3D collagen gels and in vivo in mouse skin) move superdiffusively and perform so-called L?vy walks in which step-times are drawn from probability distributions with heavy power-law tails. L?vy walk path structure is characterized by clusters of small steps separated by occasional but long """"""""flights"""""""". Importantly, it is known from the theory of stochastic processes that L?vy walks represent an optimal search strategy - one that is often employed by animal predators looking for scarce prey. In this context, metastatic cells can be viewed as """"""""cellular predators"""""""" navigating human body in a manner that maximizes their chances of finding suitable loci for seeding metastases. As we have shown, these L?vy walks can be reverted to the """"""""benign"""""""", purely diffusive walks by synergistic inhibition of Rho and Rac pathways - this finding paves the way to rationally control and ultimately limit the ability of metastatic cells to execute their predatory walks throughout the human body. Our current proposal builds on these early findings and combines experiments with theory to gain quantitative understanding of the cellular and molecular mechanisms that underlie L?vy walks of metastatic cancer cells. Specifically, micro- and nanofabrication and surface functionalization schemes will be combined to develop a microfluidic platform with which to perform parallel screens of cell motility under different conditions. Dynamic imaging of large, statistically significant numbers of cells moving on linear 1-D microtracks will be used to investigate the mechanism of L?vy walks. Molecular biology approaches including chemical inhibitors and RNA interference will be employed to perturb various parts of the actin-based motility machinery and their contribution to L?vy behavior. Rigorous statistical methodologies based on maximum likelihood estimates and Akaike weights will be used to discriminate L?vy walks from alternative motility strategies. These mechanistic studies will yield a unique dataset of conditions under which the L?vy walking phenotype can be reverted to a diffusive one. Furthermore, a predictive theoretical model will be constructed relating the status of the Rho/Rac pathways to the L?vy walking motility phenotype. We envision that the understanding and control of the L?vy walks mechanism of metastatic cells will lead to new strategies for treating metastatic cancer.
|Huda, Sabil; Pilans, Didzis; Makurath, Monika et al. (2014) Microfabricated Systems and Assays for Studying the Cytoskeletal Organization, Micromechanics, and Motility Patterns of Cancerous Cells. Adv Mater Interfaces 1:|