12 research outputs found
ROLE OF TOPOGRAPHIC CUES ON CANCER CELL PROLIFERATION
Ph.DPH.D. IN MECHANOBIOLOGY (FOS
Mechanobiology of cell migration in the context of dynamic two-way cell–matrix interactions
Migration of cells is integral in various physiological processes in all facets of life. These range from embryonic development, morphogenesis, and wound healing, to disease pathology such as cancer metastasis. While cell migratory behavior has been traditionally studied using simple assays on culture dishes, in recent years it has been increasingly realized that the physical, mechanical, and chemical aspects of the matrix are key determinants of the migration mechanism. In this paper, we will describe the mechanobiological changes that accompany the dynamic cell–matrix interactions during cell migration. Furthermore, we will review what is to date known about how these changes feed back to the dynamics and biomechanical properties of the cell and the matrix. Elucidating the role of these intimate cell–matrix interactions will provide not only a better multi-scale understanding of cell motility in its physiological context, but also a more holistic perspective for designing approaches to regulate cell behavior
Concentric gel system to study the biophysical role of matrix microenvironment on 3D cell migration
The ability of cells to migrate is crucial in a wide variety of cell functions throughout life from embryonic development and wound healing to tumor and cancer metastasis. Despite intense research efforts, the basic biochemical and biophysical principles of cell migration are still not fully understood, especially in the physiologically relevant three-dimensional (3D) microenvironments. Here, we describe an in vitro assay designed to allow quantitative examination of 3D cell migration behaviors. The method exploits the cell’s mechanosensing ability and propensity to migrate into previously unoccupied extracellular matrix (ECM). We use the invasion of highly invasive breast cancer cells, MDA-MB-231, in collagen gels as a model system. The spread of cell population and the migration dynamics of individual cells over weeks of culture can be monitored using live-cell imaging and analyzed to extract spatiotemporally-resolved data. Furthermore, the method is easily adaptable for diverse extracellular matrices, thus offering a simple yet powerful way to investigate the role of biophysical factors in the microenvironment on cell migration
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T cell activation and immune synapse organization respond to the microscale mechanics of structured surfaces
Cells have the remarkable ability to sense the mechanical stiffness of their surroundings. This has been studied extensively in the context of cells interacting with planar surfaces, a conceptually elegant model that also has application in biomaterial design. However, physiological interfaces are spatially complex, exhibiting topographical features that are described over multiple scales. This report explores mechanosensing of microstructured elastomer surfaces by CD4+ T cells, key mediators of the adaptive immune response. We show that T cells form complex interactions with elastomer micropillar arrays, extending processes into spaces between structures and forming local areas of contraction and expansion dictated by the layout of microtubules within this interface. Conversely, cytoskeletal reorganization and intracellular signaling are sensitive to the pillar dimensions and flexibility. Unexpectedly, these measures show different responses to substrate rigidity, suggesting competing processes in overall T cell mechanosensing. The results of this study demonstrate that T cells sense the local rigidity of their environment, leading to strategies for biomaterial design
Differential Depth Sensing Reduces Cancer Cell Proliferation <i>via</i> Rho-Rac-Regulated Invadopodia
Bone,
which is composed of a porous matrix, is one of the principal
secondary locations for cancer. However, little is known about the
effect of this porous microenvironment in regulating cancer cell proliferation.
Here, we examine how the depth of the pores can transduce a mechanical
signal and reduce the proliferation of noncancer breast epithelial
cells (MCF-10A) and malignant breast cancer cells (MDA-MB-231 and
MCF-7) using micrometer-scale topographic features. Interestingly,
cells extend actin-rich protrusions, such as invadopodia, to sense
the depth of the matrix pore and activate actomyosin contractility
to decrease MCF-10A proliferation. However, in MDA-MB-231, depth sensing
inactivates Rho-Rac-regulated actomyosin contractility and phospho-ERK
signaling. Inhibiting contractility on this porous matrix using blebbistatin
further reduces MDA-MB-231 proliferation. Our findings support the
notion of mechanically induced dormancy through depth sensing, where
invadopodia-mediated depth sensing can inhibit the proliferation of
noncancer and malignant breast cancer cells through differential regulation
of actomyosin contractility