title: Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion.
abstract: Tumor cell invasion requires the molecular and physical adaptation of both the cell and its microenvironment. Here we show that tumor cells are able to switch between the use of microvesicles and invadopodia to facilitate invasion through the extracellular matrix. Invadopodia formation accompanies the mesenchymal mode of migration on firm matrices and is facilitated by Rac1 activation. On the other hand, during invasion through compliant and deformable environments, tumor cells adopt an amoeboid phenotype and release microvesicles. Notably, firm matrices do not support microvesicle release, whereas compliant matrices are not conducive to invadopodia biogenesis. Furthermore, Rac1 activation is required for invadopodia function, while its inactivation promotes RhoA activation and actomyosin contractility required for microvesicle shedding. Suppression of RhoA signaling blocks microvesicle formation but enhances the formation of invadopodia. Finally, we describe Rho-mediated pathways involved in microvesicle biogenesis through the regulation of myosin light chain phosphatase. Our findings suggest that the ability of tumor cells to switch between the aforementioned qualitatively distinct modes of invasion may allow for dissemination across different microenvironments.
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556-0369, USA.
authors.forename: Alanna E
authors.initials: AE
authors.lastname: Sedgwick
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556-0369, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Clancy
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556-0369, USA.
authors.forename: M
authors.initials: M
authors.lastname: Olivia Balmert
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556-0369, USA.
authors.forename: Crislyn
authors.initials: C
authors.lastname: D'Souza-Schorey
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D000069261:Podosomes / Q000378:metabolism*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D018994:Myosin Light Chains; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D020727:ADP-Ribosylation Factors; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein