Cancer metastasis is the leading cause of cancer related deaths, but currently there are no effective treatments against it. During this process, cancer cells acquire the ability to physically invade across physiological barriers, including smal pores of the dense extracellular matrix in the tumor stroma, tight endothelial junctions during intra- and extravasation, and trafficking in the microvasculature. Cancer dissemination is highly complex, but there are many mechanical components associated with it, such as aggressive cell migration, force generation, and deformation, all of which have been linked with metastatic behavior. These properties, however, are not well understood. The challenge is that cancer mechanics exhibit many different scales that are important, including deregulation in molecular-scaled dynamics and cell-scaled invasive phenotypes. Currently there are no standardized methods that can be used to study in detail cancer metastasis across all important scales of interest. The goal of this project is to elucidate the fundamental components of the mechanics of cancer. To do this, it is necessary to develop multiscale computational and experimental tools. Specifically, we will develop Brownian dynamics simulations of motorized cytoskeletal networks in order to assess intracellular mechanics as a function of deregulation in molecular level kinetics due to cancer-induced signaling. We will further develop complementary experimental systems that will enable us to probe local mechanical properties of cancer cells in physiological conditions. This entails incorporating microrheology techniques into a 3D microfluidic platform with tunable environmental features, including flow, co-culture, and chemokine gradients. The results of this work will provide insights toward the mechanobiology of cancer that leads to metastasis and new potential therapeutic targets.
This research aims to uncover the multiscale mechanical aspects of cancer metastasis. Integrated computational and experimental systems will be developed and applied to investigate the mechanical features and capabilities that are conducive towards cancer invasion.
| Mak, Michael; Zaman, Muhammad H; Kamm, Roger D et al. (2016) Interplay of active processes modulates tension and drives phase transition in self-renewing, motor-driven cytoskeletal networks. Nat Commun 7:10323 |
| Mak, Michael; Spill, Fabian; Kamm, Roger D et al. (2016) Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics. J Biomech Eng 138:021004 |
| Mak, Michael; Kim, Taeyoon; Zaman, Muhammad H et al. (2015) Multiscale mechanobiology: computational models for integrating molecules to multicellular systems. Integr Biol (Camb) 7:1093-108 |
