Senescent stromal cells induce cancer cell migration via inhibition of RhoA/ROCK/myosin-based cell contractility

Aifuwa, Ivie; Giri, Anjil; Longe, Nick; Lee, Sang Hyuk; An, Steven S.; Wirtz, Denis

doi:10.18632/oncotarget.5854

Cited by 33 publications

(50 citation statements)

References 38 publications

(50 reference statements)

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“…Interestingly, in this model, malignant cells induce the collective invasion of epithelial cells considered to not be invasive [61]. The transformation from noninvasive to invasive phenotype was also observed in cells exposed to senescence-associated secretory phenotype (SASP), which inhibits ROCK/RhoA and promotes migration [161].…”

Section: Collective Cell Migrationmentioning

confidence: 78%

The Mechanics of Single Cell and Collective Migration of Tumor Cells

Lintz

Muñoz

Reinhart‐King

2017

Journal of Biomechanical Engineering

130

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Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.

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Section: Collective Cell Migrationmentioning

confidence: 78%

The Mechanics of Single Cell and Collective Migration of Tumor Cells

Lintz

Muñoz

Reinhart‐King

2017

Journal of Biomechanical Engineering

130

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“…RhoA promotes focal adhesion and regulates cell contractility, leading to the cell migration [ 25 ]. Wnt3a triggers RhoA activity to regulate neurite retraction of mouse neuroblastoma cells [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

PI3Kα isoform-dependent activation of RhoA regulates Wnt5a-induced osteosarcoma cell migration

et al. 2017

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BackgroundWe have reported that the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway mediated Wnt5a-induced osteosarcoma cell migration. However, the signaling pathways regulating Wnt5a/PI3K/Akt-mediated cell migration remains poorly defined in osteosarcoma cells.MethodsWe evaluated the activations of RhoA, Rac1 and Cdc42 in osteosarcoma MG-63 and U2OS cells with small G-protein activation assay. Boyden chamber assays were used to confirm the migration of cells transfected indicated constructs or siRNA specific against RhoA. A panel of inhibitors of PI3K and Akt treated osteosarcoma cells and blocked kinase activity. Western blotting and RhoA activation assay were employed to measure the effect of kinase inhibitors and activations of RhoA and Akt.ResultsWe found that Wnt5a had a potent stimulatory effect on RhoA activation, but not on Rac1 and Cdc42 activations. Wnt5a-induced cell migration was largely abolished by siRNA specific against RhoA. DN-RhoA (GFP-RhoA-N19) was also capable of retarding Wnt5a-induced cell migration, but the overexpression of CA-RhoA (GFP-RhoA-V14) was not able to accelerate cell migration. The Wnt5a-induced activation of RhoA was mostly blocked by pretreatment of LY294002 (PI3K inhibitor) and MK-2206 (Akt inhibitor). Furthermore, we found that the Wnt5a-induced activation of RhoA was mostly blocked by pretreatment of HS-173 (PI3Kα inhibitor). Lastly, the phosphorylation of Akt (p-Ser473) was not altered by transfection with siRNA specific against RhoA or DN-RhoA (GFP-RhoA-N19).ConclusionsTaken together, we demonstrate that RhoA acts as the downstream of PI3K/Akt signaling (specific PI3Kα, Akt1 and Akt2 isoforms) and mediated Wnt5a-induced the migration of osteosarcoma cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0396-8) contains supplementary material, which is available to authorized users.

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“…It has been recently shown that the SASP from senescent stromal fibroblasts inhibits the RhoA/ROCK/myosin-dependent cell contractility leading to aggressive cell motility in human breast cancer cells [48]. However, the exact key SASP factors and the mechanisms involved in cSCC cell migration have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

et al. 2016

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Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression. Whereas the Chemerin abundance is downregulated in malignant cSCC cells, increased Chemerin transcripts and protein concentrations are detected in replicative senescent fibroblasts in vitro and in the fibroblast of skin sections from old donors, indicating that a Chemerin gradient is built up in the dermis of elderly. Using Transwell® migration assays, we show that Chemerin enhances the chemotaxis of different cSCC cell lines. Notably, the Chemerin receptor CCRL2 is remarkably upregulated in cSCC cell lines and human patient biopsies. Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis. Chemerin triggers the MAPK cascade via JNK and ERK1 activation, whereby the inhibition impairs the SASP- or Chemerin-mediated cSCC cell migration.Taken together, we uncover a key role for Chemerin, as a major factor in the secretome of senescent fibroblasts, promoting cSCC cell migration and possibly progression, relaying its signals through CCRL2 and GPR1 receptors with subsequent MAPK activation. These findings might have implications for targeted therapeutic interventions in elderly patients.

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Senescent stromal cells induce cancer cell migration via inhibition of RhoA/ROCK/myosin-based cell contractility

Cited by 33 publications

References 38 publications

The Mechanics of Single Cell and Collective Migration of Tumor Cells

The Mechanics of Single Cell and Collective Migration of Tumor Cells

PI3Kα isoform-dependent activation of RhoA regulates Wnt5a-induced osteosarcoma cell migration

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

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