ROCK- and Myosin-Dependent Matrix Deformation Enables Protease-Independent Tumor-Cell Invasion In Vivo

Wyckoff, Jeffrey; Pinner, Sophie; Gschmeissner, Steve; Condeelis, John S.; Sahai, Erik

doi:10.1016/j.cub.2006.05.065

Cited by 402 publications

(457 citation statements)

References 29 publications

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“…Migrating cells exert traction force upon their surroundings, 26,27 and cell traction force is necessary in cancer cell migration and invasion. 28,29 Fourier transform traction microscopy showed that stably LAMC2-transfected A549R0 cells were bigger in size (Po0.05) and exhibited greater cell traction force (Figure 2e), with~1.5-fold higher (Po0.05) net contractile moment compared with mock control. Similar results were observed in A549R3-Brain and A549R4-Femur cells as compared with A549R0 cells (Supplementary Figure S2B).…”

Section: Resultsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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Section: Resultsmentioning

confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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“…Given the critical role of actomyosin contractility in amoeboid migration (Wyckoff et al, 2006), together with the fact that Tm5NM1 causes increased myosin II activity (Bryce et al, 2003), it is surprising that Tm5NM1 does not cause cells to transit to an amoeboid phenotype. Importantly, amoeboid motility is highly dependant on extensive reorganization of the actin cytoskeleton (Eichinger et al, 1999;Sahai, 2007;Kitzing et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The protease inhibitor (PI) cocktail contained E-64 (Sigma, St Louis, MO, USA), Pepstatin A (Sigma), Leupeptin (Sigma), Aprotinin (Sigma) and Marimastat (Tocris Bioscience, Ellisville, MO, USA); concentrations used were those previously described to induce mesenchymal to amoeboid migration . The Rho kinase inhibitor Y-27632 (Sigma) was used at 10 mM, a concentration previously described to inhibit Rho kinase activity (Wyckoff et al, 2006). Sheep polyclonal anti-g/9d antibody was used to detect exon 9D containing tropomyosins isoforms (Tm5NM1/2), and mouse anti-a/9d antibody was used to detect Tms 1, 2, 3, 5a and 5b as previously described .…”

Section: Methodsmentioning

confidence: 99%

The actin-associating protein Tm5NM1 blocks mesenchymal motility without transition to amoeboid motility

et al. 2010

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Cell migration is an integral component of metastatic disease. The ability of cells to transit between mesenchymal and amoeboid modes of migration has complicated the development of successful therapies designed to target cell migration as a means of inhibiting metastasis. Therefore, investigations of the mechanisms that regulate cell migration and render cells stationary are necessary. Tropomyosins are actin-associating proteins that regulate the activity of several effectors of actin filament dynamics. Previously, we have shown that the tropomyosin isoform Tm5NM1 stabilizes actin filaments and inhibits cell migration in a two-dimensional culture system. Here, we show that Tm5NM1 inhibits the mesenchymal migration of multiple cell lines in an isoform-specific manner. Tm5NM1 stimulates the downregulation of Src kinase activity and a rounded or elliptical morphology in threedimensional collagen gels, and cells have dramatically reduced capacity to form pseudopodia. Importantly, we find that Tm5NM1 inhibits both the mesenchymal to amoeboid and amoeboid to mesenchymal transitions. Collectively, our data suggest that mimicking the action of Tm5NM1 overexpression represents an approach for effectively inhibiting the mesenchymal mode of migration.

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“…Mesenchymal motility is dependent on integrins and proteases, such as MMPs (matrix metalloproteinases), whereas amoeboid motility is dependent on the ROCK/Rho kinase. The latter phosphorylates the myosin-II light chain and consequently leads to actomyosin contractility, and this process that is independent of protease activity Sabeh et al, 2004;Wilkinson et al, 2005;Carragher et al, 2006;Paluch et al, 2006;Torka et al, 2006;Wyckoff et al, 2006;Sahai et al, 2007;Fackler and Grosse, 2008). Mesenchymal motility can also switch to amoeboid motility if pericellular proteolysis is blocked by treatment with protease inhibitors (Wolf et al, , 2007Carragher et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates

2009

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The motility of cancer cells in 3D matrices is of two types: mesenchymal motility, in which the cells are elongated and amoeboid motility, in which the cells are round. Amoeboid motility is driven by an actomyosin-based contractile force, which is regulated by the Rho/ROCK pathway. However, the molecular mechanisms underlying the motility of elongated cells remain unknown. Here, we show that the motility of elongated cells is regulated by Rac signaling through the WAVE2/Arp2/3-dependent formation of elongated pseudopodia and cell-substrate adhesion in 3D substrates. The involvement of Rac signaling in cell motility was different in cell lines that displayed an elongated morphology in 3D substrates. In U87MG glioblastoma cells, most of which exhibit mesenchymal motility, inhibition of Rac signaling blocked the invasion of these cells in 3D substrates. In HT1080 fibrosarcoma cells, which display mixed cell motility involving both elongated and rounded cells, inhibition of Rac1 signaling not only blocked mesenchymal motility but also caused a mesenchymalamoeboid transition. Additionally, Rac1 and RhoA signaling regulated the mesenchymal and amoeboid motility in these cells, respectively, and the inhibition of both pathways dramatically decreased cell invasion. Hence, we could conclude that Rac1 and RhoA signaling simultaneously regulate cell invasion in 3D matrices.

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ROCK- and Myosin-Dependent Matrix Deformation Enables Protease-Independent Tumor-Cell Invasion In Vivo

Cited by 402 publications

References 29 publications

LAMC2 enhances the metastatic potential of lung adenocarcinoma

LAMC2 enhances the metastatic potential of lung adenocarcinoma

The actin-associating protein Tm5NM1 blocks mesenchymal motility without transition to amoeboid motility

Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates

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