Metastasis of aggressive amoeboid sarcoma cells is dependent on Rho/ROCK/MLC signaling

Kosla, Jan; Paňková, Daniela; Plachý, Jiřı́; Tolde, Ondřej; Bicanova, Kristyna; Dvořák, Michal; Rösel, Daniel; Brábek, Jan

doi:10.1186/1478-811x-11-51

Cited by 36 publications

(28 citation statements)

References 32 publications

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“…The transition to amoeboid motility (mesenchymal‐to‐amoeboid transition; MAT), can be induced experimentally by inhibiting metalloproteinase activity [Wolf et al., 2003a,b; Kosla et al., ; Taddei et al., ], disrupting cell–substrate adhesions [Wolf et al., ; Carragher et al., ; Van Goethem et al., ; Ehrbar et al., ; Liu et al., ], inhibiting Arp2/3 complex‐dependent actin polymerisation in lamellipodia [Derivery et al., ; Bergert et al., ; Beckham et al., ], or shifting a balance between actin polymerisation‐driven protrusion and actomyosin‐dependent contractility by altering Rho‐family small GTPases activity [Sahai and Marshall, ; Sanz‐Moreno, V., ; Parri et al., ; Bergert et al., ]. Thus, it appears that under conditions unfavourable for lamellipodium formation, some tumour cells switch to amoeboid motility to bypass the inhibition which leads to greater autonomy of cell migration.…”

Section: Introductionmentioning

confidence: 99%

Transition from mesenchymal to bleb‐based motility is predominantly exhibited by CD133‐positive subpopulation of fibrosarcoma cells

Chikina

Rubtsova²,

Lomakina³

et al. 2019

Biology of the Cell

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Background Information Metastatic disease is caused by the ability of cancer cells to reach distant organs and form secondary lesions at new locations. Dissemination of cancer cells depends on their migration plasticity – an ability to switch between motility modes driven by distinct molecular machineries. One of such switches is mesenchymal‐to‐amoeboid transition. Although mesenchymal migration of individual cells requires Arp2/3‐dependent actin polymerisation, amoeboid migration is characterised by a high level of actomyosin contractility and often involves the formation of membrane blebs. The acquisition of amoeboid motility by mesenchymal cells is often associated with enhanced metastasis. Results We studied the ability of mesenchymal HT1080 fibrosarcoma cells to switch to amoeboid motility. We induced the transition from lamellipodium‐rich to blebbing phenotype either by down‐regulating the Arp2/3 complex, pharmacologically or by RNAi, or by decreasing substrate adhesiveness. Each of these treatments induced blebbing in a subset of fibrosarcoma cells, but not in normal subcutaneous fibroblasts. A significant fraction of HT1080 cells that switched to blebbing behaviour exhibited stem cell‐like features, such as expression of the stem cell marker CD133, an increased efflux of Hoechst‐33342 and positive staining for Oct4, Sox2 and Nanog. Furthermore, the isolated CD133+ cells demonstrated an increased ability to switch to bleb‐rich amoeboid phenotype both under inhibitor's treatment and in 3D collagen gels. Conclusions Together, our data show a significant correlation between the increased ability of cells to switch between migration modes and their stem‐like features, suggesting that migration plasticity is an additional property of stem‐like population of fibrosarcoma cells. This combination of features could facilitate both dissemination of these cells to distant locations, and their establishment self‐renewal in a new microenvironment, as required for metastasis formation. Significance These data suggest that migration plasticity is a new feature of cancer stem‐like cells that can significantly facilitate their dissemination to a secondary location by allowing them to adapt quickly to challenging microenvironments. Moreover, it complements their resistance to apoptosis and self‐renewal potential, thus enabling them not only to disseminate efficiently, but also to survive and colonise new niches.

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Section: Introductionmentioning

confidence: 99%

Transition from mesenchymal to bleb‐based motility is predominantly exhibited by CD133‐positive subpopulation of fibrosarcoma cells

Chikina

Rubtsova²,

Lomakina³

et al. 2019

Biology of the Cell

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“…ROCK and MRCK have been shown to phosphorylate MLC and have been implicated in regulation of cell contractility [15][16][17]. The amoeboid mode of invasion is primarily dependent on ROCK activity to generate strong contractile forces and is independent of protease activity [18][19][20], whereas the mesenchymal mode of cell invasion depends on the activity of MRCK to generate contractile forces [21]. Importantly, studies demonstrate that cancer cells often switch between these two mechanisms when an individual mode of migration/invasion is blocked (reviewed in Refs.…”

Section: Introductionmentioning

confidence: 99%

A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

et al. 2014

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Two structurally related protein kinase families, the Rho kinases (ROCK) and the myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK) are required for migration and invasion of cancer cells. We hypothesized that simultaneous targeting of these two kinase families might represent a novel therapeutic strategy to block the migration and invasion of metastatic cancers. To this end, we developed DJ4 as a novel small molecule inhibitor of these kinases. DJ4 potently inhibited activities of ROCK and MRCK in an ATP competitive manner. In cellular functional assays, DJ4 treatment significantly blocked stress fiber formation and inhibited migration and invasion of multiple cancer cell lines in a concentration dependent manner. Our results strongly indicate that DJ4 may be further developed as a novel anti-metastatic chemotherapeutic agent for multiple cancers.

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“…Our results indicated that the model can be used to identify sarcoma patients at high risk and enabling early interventions to improve the prognosis. Among 19 IRGs enrolled in risk signature, VEGFA, CYR61, and RHOA have con rmed to be related to the pathogenesis or prognosis of sarcoma [38][39][40][41]. It was reported that VEGFA is a potential neovascular regulatory factor that promotes tumor growth and metastasis through its receptor.…”

Section: Discussionmentioning

confidence: 99%

“…The expression level of CYR61 is associated with the aggressiveness of osteosarcoma in different pre-clinical models and patient tumor samples, and CYR61 triggers osteosarcoma metastasis and spread through an IGF1Rβ-dependent EMTlike process [44]. The metastasis of invasive amoebic sarcoma cells depends on the Rho / Rock / MLC signal, and RHOA overexpression is related to tumor cell invasion and migration [41]. The relationship between the remaining 16 genes and sarcoma has few been reported, however, most of them have been con rmed to be associated with other tumors, which suggested that these genes also play essential roles in sarcoma.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma

Shen

Meng

et al. 2020

Preprint

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Background Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs. Methods We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed. Results A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis(P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs. Conclusions In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets.

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Metastasis of aggressive amoeboid sarcoma cells is dependent on Rho/ROCK/MLC signaling

Cited by 36 publications

References 32 publications

Transition from mesenchymal to bleb‐based motility is predominantly exhibited by CD133‐positive subpopulation of fibrosarcoma cells

Transition from mesenchymal to bleb‐based motility is predominantly exhibited by CD133‐positive subpopulation of fibrosarcoma cells

A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma

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