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Abstract This work presents the development of a novel approach to model cancer cell dynamics in microcirculation. The proposed numerical model is based on a hybrid continuum-particle approach. The cancer cell model includes the cell membrane, nucleus, cytoplasm and the cytoskeleton. The Dissipative Particle Dynamics method was employed to simulate the mechanical components. The blood plasma is modeled as a Newtonian incompressible fluid. A Fluid-Structure Interaction coupling, leveraging the Immersed Boundary Method is developed to simulate the cell's response to flow dynamics. The model is applied to resolve the transport of cancer cells with realistic morphologies in microcirculatory flows. Our results suggest that the controlling of oscillatory flows can be utilized to induce specific morphological shapes and the surrounding fluid patterns, allowing full manipulation and control of the cell. Furthermore, the intracellular and extracellular dynamics response of the cancer cell is intrinsically linked to their shape, in which certain morphologies displayed strong resistance to the fluid-induced forces and the ability to migrate in various directions. Our computational framework provides new capabilities for designing bioengineering devices for cell manipulation and separation. 

Cells are adept at sensing changes in their environment, transmitting signals internally to coordinate responses to external stimuli, and thereby influencing adaptive changes in cell states and behavior. Often, this response involves modulation of gene expression in the nucleus, which is seen largely as a physically separated process from the rest of the cell. Mechanosensing, whereby a cell senses physical stimuli, and integrates and converts these inputs into downstream responses including signaling cascades and gene regulatory changes, involves the participation of several macromolecular structures. Of note, the extracellular matrix (ECM) and its constituent macromolecules comprise an essential part of the cellular microenvironment, allowing cells to interact with each other, and providing both structural and biochemical stimuli sensed by adhesion transmembrane receptors. This highway of information between the ECM, cell adhesion proteins, and the cytoskeleton regulates cellular behavior, the disruption of which results in disease. Emerging evidence suggests a more direct role for some of these adhesion proteins in chromatin structure and gene regulation, RNA maturation and other non-canonical functions. While many of these discoveries were previously limited to observations of cytoplasmic-nuclear transport, recent advances in microscopy, and biochemical, proteomic and genomic technologies have begun to significantly enhance our understanding of the impact of nuclear localization of these proteins. This review will briefly cover known cell adhesion proteins that migrate to the nucleus, and their downstream functions. We will outline recent advances in this very exciting yet still emerging field, with impact ranging from basic biology to disease states like cancer. 

Abstract We performed the transport of a breast cancer cell (MB231-TGFb) in a microvessel using high-resolution simulations. Using open-source imaging software Slicer3D and Meshmixer, the 3D surface mesh forming the cell membrane was reconstructed from confocal microscopic images. The Dissipative Particle Dynamics method is used to model the cell membrane. The extracellular fluid flow is modeled with the Immersed Boundary Method to solve the governing equations of the blood plasma. The unsteady flow is applied at the inlet of the microchannel with an oscillatory pattern. Our results showed that the extracellular flow patterns are highly dependent on the waveform profile. The oscillatory flow showed the creation of vortices that influence the cellular deformations in the microchannel. These results could have implications on the destination of the cancer cells during transport in physiological flows. 

Integrin, as a mechanotransducer, establishes the mechanical reciprocity between the extracellular matrix (ECM) and cells at integrin-mediated adhesion sites. This study used steered molecular dynamics (SMD) simulations to investigate the mechanical responses of integrinα_vβ₃with and without 10th type III fibronectin (FnIII₁₀) binding for tensile, bending and torsional loading conditions. The ligand-binding integrin confirmed the integrin activation during equilibration and altered the integrin dynamics by changing the interface interaction between β-tail, hybrid and epidermal growth factor domains during initial tensile loading. The tensile deformation in integrin molecules indicated that fibronectin ligand binding modulates its mechanical responses in the folded and unfolded conformation states. The bending deformation responses of extended integrin models reveal the change in behaviour of integrin molecules in the presence of Mn²⁺ion and ligand based on the application of force in the folding and unfolding directions of integrin. Furthermore, these SMD simulation results were used to predict the mechanical properties of integrin underlying the mechanism of integrin-based adhesion. The evaluation of integrin mechanics provides new insights into understanding the mechanotransmission (force transmission) between cells and ECM and contributes to developing an accurate model for integrin-mediated adhesion. This article is part of a discussion meeting issue ‘Supercomputing simulations of advanced materials’.