Research Project
10271569
Computational Core (Core A): SUMMARY To guide and interpret the in vitro (Project 1) and in vivo experiments (Project 2) and to provide a physical basis for changes in transcriptional patterns in response to mechanical stresses (Core B), this core will employ an array of computational tools spanning a wide range of length and time scales. These include models for cell adhesion, cytoskeletal function, cell-matrix interactions and 3D multiscale models for nuclear mechano- transduction and chromatin organization. This suite of modeling tools will reveal non-linear interactions between cell and nuclear deformation during of extravasation and migration, mechano-adaptation in response to fluid and solid stresses, intravascular and extravascular niche properties and cell death for individual compared to clustered CTCs. Significantly, modelling of 3D genome organization will allow us to elucidate the relationship between the mechanics of the cell, chromatin organization, and transcription, thus providing new insights on how mechanical stresses regulate gene expression during metastasis, and identification of reversible and persisting chromatin deformation associates with cell survival or death. Cancer cells invade individually or collectively, but the factors that govern their strategies to colonize the tissue and their ability to survive intravascular stress and extravasation are poorly understood. While the coupling between cell contractility, nuclear mechanotransduction, and adhesive interactions with the ECM and vessel wall is known to affect cell adhesion and motility, the effects of this interplay on cell survival has yet to be rigorously investigated. To elucidate the physical mechanisms involved in such regulation, we developed 3D chemo- mechanical models to describe the three-way feedback between the adhesions, the cytoskeleton, and the nucleus. The model shows local tensile stresses generated at the interface of the cell and the extracellular environment regulate the properties of the nucleus, including nuclear morphology, levels of lamin A/C, histone deacetylation and nucleo-cytoplasmic shuttling of YAP/TAZ, which in turn govern spatial chromatin organization, gene expression and the ability of the cells to survive and cope with the mechanical stresses. Building on these tools, the specific aims of this project are: · Aim 1. Predict the role of vascular flow on tumor cell arrest and survival in the intravascular niche. · Aim 2. Model the mechanochemical/molecular mechanisms of individual/collective extravasation of CTCs. · Aim 3. Predict the influence of alterations in chromatin organization and transcriptional patterns induced by intravascular stress and extravasation on the survival and growth of migrating tumor cells
