"Quantitative Analysis of 2D and 3D Models for Epidermal Growth Factor Receptor-Dependent Cell Migration in the Context of the Extracellular Microenvironment"
Current models of the early stages of tumor metastasis suggest that carcinomas undergo an epithelial-mesenchymal-transition to become motile and invade complex neighboring tissue consisting of the 3D extracellular matrix. This invasion environment consists of multiple biochemical and biophysical cues that affects the success of tumor cell invasion. The epidermal growth factor receptor (EGFR) expression is correlated with tumor progression and invasiveness in many cancers and is in the center of regulating the invasion process. Due to the multivariate nature of this process, the detailed analysis of cell migration in the context of the invasion microenvironment compels a quantitative approach. My work involves assessing EGFR dependent cell migration in the context of various extracellular cues.
In the first part of my work, we analyzed the effects of the 3D matrix environment on cell migration and addressed effects of matrix proteolysis and matrix micro-architecture on the migratory parameters, such as cell speed and directional persistence. We demonstrate that quantitative parsing of cell-intrinsic and cell-extrinsic effects allows the discovery of matrix proteolysis as a novel regulator of directional persistence in a 3D matrix environment. Using porous biomaterials and careful variation of their parameters, we establish the junction micro-architecture as an additional factor in regulating cell migration, which is of importance for tumor cell migration along aligned fibers observed in many instances.
Currently, we are analyzing EGFR-dependent cell migration in the context of the epithelial-mesenchymal-transition using a quantitative multivariate modeling approach relating signaling and migration responses.
Philippar U, Roussos ET, Oser M, Yamaguchi H, Kim HD, Giampieri S, Wang Y, Goswami S, Wyckoff JB, Lauffenburger DA, Sahai E, Condeelis JS, Gertler FB. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev Cell. 2008 Dec;15(6):813-28.
Kim HD, Guo TW, Wu AP, Wells A, Gertler FB, Lauffenburger DA. Epidermal growth factor-induced enhancement of glioblastoma cell migration in 3D arises from an intrinsic increase in speed but an extrinsic matrix- and proteolysis-dependent increase in persistence. Mol Biol Cell. 2008 Oct;19(10):4249-59. DOI
Harley BA, Kim HD, Zaman MH, Yannas IV, Lauffenburger DA, Gibson LJ. Microarchitecture of three-dimensional scaffolds influences cell migration behavior via junction interactions. Biophys J. 2008 Oct;95(8):4013-24.
Kumar N, Afeyan R, Kim HD, Lauffenburger DA. Multipathway model enables prediction of kinase inhibitor cross-talk effects on migration of Her2-overexpressing mammary epithelial cells. Mol Pharmacol. 2008 Jun;73(6):1668-78.
Wolf-Yadlin A, Kumar N, Zhang Y, Hautaniemi S, Zaman M, Kim HD, Grantcharova V, Lauffenburger DA, White FM. Effects of HER2 overexpression on cell signaling networks governing proliferation and migration. Mol Syst Biol. 2006;2:54.
Kumar N, Zaman MH, Kim HD, Lauffenburger DA. A high-throughput migration assay reveals HER2-mediated cell migration arising from increased directional persistence. Biophys J. 2006 Aug 15;91(4):L32-4.