Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization.
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.
Provenzano
Paolo P
PP
Department of Pharmacology, Laboratory of Molecular Biology, University of Wisconsin Paul P Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin 53706, USA. ppproven@wisc.edu
Inman
David R
DR
Eliceiri
Kevin W
KW
Trier
Steven M
SM
Keely
Patricia J
PJ
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
D003094:Collagen; D054460:rho-Associated Kinases; D010447:Peptide Hydrolases; D020741:rho GTP-Binding Proteins
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