LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition in 3D matrices

Naotsuka, Moyu; Horita, Yuji; Sato, Masaaki; Ohashi, Kazumasa; Mizuno, Kensaku

doi:10.1016/j.bbrc.2010.01.075

Cited by 27 publications

(19 citation statements)

References 25 publications

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“…S3a. Our model is consistent with the experiments showing that cells with constitutively active RhoA are associated with amoeboid (A) or blebby amoeboid (BA) phenotype46; while cells with dominant negative RhoA usually exhibit a mesenchymal (M) phenotype10. It also predicted that, when the external signal acts only on RhoA, the induced transitions between A and M phenotypes are much easier than the transitions from A or M phenotype to A/M or E/M phenotype.…”

Section: Introductionsupporting

confidence: 89%

The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition

Huang

Jolly

et al. 2014

Sci Rep

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Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal. This plasticity poses a major clinical challenge for treating metastasis, while its underlying mechanisms remain enigmatic. Transitions between these phenotypes are mediated by the Rac1/RhoA circuit that responds to external signals such as HGF/SF via c-MET pathway. Using detailed modeling of GTPase-based regulation to study the Rac1/RhoA circuit's dynamics, we found that it can operate as a three-way switch. We propose to associate the circuit's three possible states to the amoeboid, mesenchymal and amoeboid/mesenchymal hybrid phenotype. In particular, we investigated the range of existence of, and the transition between, the three states (phenotypes) in response to Grb2 and Gab1 - two downstream adaptors of c-MET. The results help to explain the regulation of metastatic cells by c-MET pathway and hence can contribute to the assessment of possible clinical interventions.

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Section: Introductionsupporting

confidence: 89%

The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition

Huang

Jolly

et al. 2014

Sci Rep

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“…Accordingly, earlier studies including ours clearly demonstrated an important role of LIMK1 in induction of invasion and metastasis of prostate and breast cancer cells and tumors [2-4]. More recently, role of LIMK1 in induction of metastasis in pancreatic cancer in zebrafish xenograft assays [42]; and mesenchymal and ameboid modes of invasion of fibrosarcoma cells in 3D matrices [43,44] were shown. These studies further strengthened the importance of LIMK1 and Rho/Rock signaling pathway in generation of protrusive forces of tumor cells through collagen matrices.…”

Section: Discussionmentioning

confidence: 56%

LIM kinase1 modulates function of membrane type matrix metalloproteinase 1: implication in invasion of prostate cancer cells

2011

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BackgroundLIM kinase 1 (LIMK1) is an actin and microtubule cytoskeleton modulatory protein that is overexpressed in a number of cancerous tissues and cells and also promotes invasion and metastasis of prostate and breast cancer cells. Membrane type matrix metalloproteinase 1 (MT1-MMP) is a critical modulator of extracellular matrix (ECM) turnover through pericellular proteolysis and thus plays crucial roles in neoplastic cell invasion and metastasis. MT1-MMP and its substrates pro-MMP-2 and pro-MMP-9 are often overexpressed in a variety of cancers including prostate cancer and the expression levels correlate with the grade of malignancy in prostate cancer cells. The purpose of this study is to determine any functional relation between LIMK1 and MT1-MMP and its implication in cell invasion.ResultsOur results showed that treatment with the hydroxamate inhibitor of MT1-MMP, MMP-2 and MMP-9 ilomastat inhibited LIMK1-induced invasion of benign prostate epithelial cells. Over expression of LIMK1 resulted in increased collagenolytic activity of MMP-2, and secretion of pro-MMP2 and pro-MMP-9. Cells over expressing LIMK1 also exhibited increased expression of MT1-MMP, transcriptional activation and its localization to the plasma membrane. LIMK1 physically associates with MT1-MMP and is colocalized with it to the Golgi vesicles. We also noted increased expression of both MT1-MMP and LIMK1 in prostate tumor tissues.ConclusionOur results provide new information on regulation of MT1-MMP function by LIMK1 and showed for the first time, involvement of MMPs in LIMK1 induced cell invasion.

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“…The mesenchymal-amoeboid transition is induced by overexpression of LIM domain kinase 1 (LIMK1) gene that induced cell rounding. Thus, these results suggest that LIMK1 plays an important role in the Rho/ROCK-induced mesenchymal-to-amoeboid cell morphological transition of human fibrosarcoma HT1080 cells cultured in 3D collagen matrices [61].…”

Section: Invasion Modes Regulate Cancer Cell Motilitymentioning

confidence: 98%

“…The transition of tumors plays a role in different stages of tumor progression, while the epithelial-mesenchymal transition requires the transcriptional regulation of gene expression, the mesenchymal-amoeboid or amoeboidmesenchymal transition can react faster to certain alterations of the microenvironment that facilitate both morphological and functional adaption of cancer cells to invade the ECM [61]. The mesenchymal-amoeboid transition is induced by overexpression of LIM domain kinase 1 (LIMK1) gene that induced cell rounding.…”

Section: Invasion Modes Regulate Cancer Cell Motilitymentioning

confidence: 99%

The Biomechanical Properties of 3d Extracellular Matrices and Embedded Cells Regulate the Invasiveness of Cancer Cells

Mierke

2011

Cell Biochem Biophys

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The malignancy of tumors depends on the biomechanical properties of cancer cells and their microenvironment, which enable cancer cells to migrate through the connective tissue, transmigrate through basement membranes and endothelial monolayers and form metastases in targeted organs. The current focus of cancer research is still based on biological capabilities such as molecular genetics and gene signaling, but these approaches ignore the mechanical nature of the invasion process of cancer cells. This review will focus on how structural, biochemical and mechanical properties of extracellular matrices (ECMs), and adjacent cells regulate the invasiveness of cancer cells. In addition, it presents how cancer cells create their own microenvironment by restructuring of the ECM and by interaction with stromal cells, which then further contribute to the progression of cancer disease. Finally, this review will point out that mechanical properties are a critical determinant for the efficiency of cancer cell invasion and the progression of cancer which might affect the future development of new cancer treatments.

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LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition in 3D matrices

Cited by 27 publications

References 25 publications

The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition

The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition

LIM kinase1 modulates function of membrane type matrix metalloproteinase 1: implication in invasion of prostate cancer cells

The Biomechanical Properties of 3d Extracellular Matrices and Embedded Cells Regulate the Invasiveness of Cancer Cells

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