Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization

Paolo P. Provenzano, David R. Inman, Kevin W. Eliceiri, Steven M. Trier, Patricia J. Keely

Research output: Contribution to journalArticlepeer-review

344 Scopus citations

Abstract

Cells generate mechanical force to organize the extracellular matrix (ECM) and drive important developmental and reparative processes. Likewise, tumor cells invading into three-dimensional (3D) matrices remodel the ECM microenvironment. Importantly, we previously reported a distinct radial reorganization of the collagen matrix surrounding tumors that facilitates local invasion. Here we describe a mechanism by which cells utilize contractility events to reorganize the ECM to provide contact guidance that facilitates 3D migration. Using novel assays to differentially organize the collagen matrix we show that alignment of collagen perpendicular to the tumor-explant boundary promotes local invasion of both human and mouse mammary epithelial cells. In contrast, organizing the collagen matrix to mimic the ECM organization associated with noninvading regions of tumors suppresses 3D migration/invasion. Moreover, we demonstrate that matrix reorganization is contractility-dependent and that the Rho/Rho kinase pathway is necessary for collagen alignment to provide contact guidance. Yet, if matrices are prealigned, inhibiting neither Rho nor Rho kinase inhibits 3D migration, which supports our conclusion that Rho-mediated matrix alignment is an early step in the invasion process, preceding and subsequently facilitating 3D migration.

Original languageEnglish (US)
Pages (from-to)5374-5384
Number of pages11
JournalBiophysical journal
Volume95
Issue number11
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants from the U.S. Department of Defense-CDMRP/BCRP: W81XWH-04-1-0428 (P.P.P.), National Institutes of Health-National Cancer Institute: R01-CA076537 and American Cancer Society: RSG-00-339CSM (P.J.K.), and National Institutes of Health-National Institute of Biomedical Imaging and BioEngineering : R01-EB000184 (K.W.E.).

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