Cell-Matrix Interactions and Migration

National Institute Of Dental & Craniofacial Research

Investigators

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Abstract

Extracellular matrix molecules, integrin receptors, cadherins, cytoskeletal proteins, and regulators of these molecular systems contribute to cell migration and signaling by complex, integrated mechanisms. We are addressing the following specific questions: 1. What biophysical phenomena and signaling mechanisms are important for efficient cell migration in three-dimensional environments? 2. How are the functions of integrins, cadherins, the extracellular matrix, and the cytoskeleton integrated, and how is the regulatory crosstalk between them coordinated to produce effective cell migration? We are using a variety of cell and molecular biology approaches to address these questions, including live-cell wide-field, confocal, and two-photon time-lapse microscopy with fluorescent protein chimeras, biochemical and signal transduction analyses, as well as methods for evaluating local matrix deformations in response to forces from individual migrating mammalian cells. We use a variety of fluorescent molecular chimeras and mutants of cytoskeletal proteins as part of a long-term program to analyze their functions in integrin-mediated processes. We have been focusing particularly on the functions and regulation of specific integrins and their associated extracellular and intracellular molecules in the mechanisms and spatial governance of cell migration. A series of studies of non-malignant versus cancer cells has been focusing on the biophysical mechanisms of efficient cell migration in collagen matrices to partially mimic in vivo connective tissues. The dynamic interactions of cells as they apply forces to a matrix while migrating has been characterized using particle image velocimetry (PIV), which permits quantitative measurements of matrix fibril displacement using confocal microscopy time-lapse movies of normal versus cancer cells. We are continuing to analyze in further detail the mechanisms of cell-matrix adhesion formation in a 3D microenvironment. We have been developing an ex vivo model system for analyzing cell interactions and migration in a physiological 3D environment to complement our studies on cell-matrix interactions in vitro. This current work is focusing on mouse fascia as a source of native extracellular matrix with refinement of technical approaches to make its use practical. In vivo studies of cell interactions in living Drosophila embryos with a model of tumor progression has revealed that the recruitment of macrophage-like immune cells to tumors is dependent on the level of non-apoptotic caspase signaling. This migration to, and accumulation of, immune cells at a tumor has properties that mimic a chronic wound, and it contributes to tumor progression that can be inhibited by non-apoptotic caspase functions. This combined approach involving mechanistic characterization of the regulation of cell migration and phenotypes in various microenvironments should provide novel approaches to understanding, preventing, or ameliorating migratory processes used by cells during abnormal embryonic development, as well as in cancer invasion. An in-depth understanding of the precise manner by which cells move and interact with their extracellular matrix environment, e.g., during embryonic development, should also facilitate tissue engineering studies in future regenerative medicine.