SU-E-J-41: Computational and Experimental Analysis of Cancer Cell Mechanics in 3D: Intracellular Viscoelasticity and Internal Stresses

Authors


Abstract

Purpose:

We develop an integrated multiscale experimental and computational system to bridge the mechanics and kinetics of motors in crosslinked actin-networks at the molecular scale with cell-scaled tensional dynamics in 3D. We investigate the intracellular viscoelastic properties of invasive breast cancer cells in a 3D-matrix with a tunable microfluidic device that enables the generation of flow and gradients as well as co-culture conditions.

Methods:

For computational analyses, we use a custom Brownian dynamics model of F-actin networks with dynamic crosslinking proteins and active myosin motors to simulate internal stress generation and motor-induced cytoskeletal remodeling. For experimentation, we develop a system that integrates a highly customizable microfluidic device for 3D cell culture with intracellular particle-tracking microrheology to study intracellular viscoelasticity of cells in 3D.

Results:

Our results demonstrate that a balance between crosslinker density, actin polymerization and nucleation dynamics, and motor kinetics and density control intracellular morphology and tension. Experimentally, we show that intracellular viscoelasticity appears to be anisotropic and heterogeneous, and we compare the shear moduli of cells in 2D and 3D. Additionally, we show that altered polymerization dynamics lead to altered cytoskeletal morphologies that appear more aggregated, consistent with our simulations that show motorinduced cytoskeletal remodeling when actin assembly and disassembly rates are not sufficiently high.

Conclusion:

A multiscale approach that bridges molecular-scaled dynamics with single and multicellular networks in 3D physiological environments can be an enabling method for understanding the physical and mechanical phenomena that govern cell force generation, migration, and cancer invasion and dissemination. By understanding how molecular mechanical mechanisms translate into metastatic behavior of cells, we can then begin to identify in a rigorous manner new therapeutics that target the functional and physical properties of cancer cells. Specifically, our approach allows for the fundamental elements that give rise to intracellular structure and tension to be investigated.

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