Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation

Mouneimne, Ghassan; Soon, Lilian; DesMarais, Vera; Sidani, Mazen; Song, Xian‐Rong; Yip, Shu Chin; Ghosh, Mousumi; Eddy, Robert J.; Backer, Jonathan M.; Condeelis, John S.

doi:10.1083/jcb.200405156

Cited by 213 publications

(321 citation statements)

References 56 publications

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“…However, given that there are four regulatory mechanisms for cofilin activity that appear to be uncoupled, the activity status of cofilin in a cell cannot be assessed by measuring the ratio of dephosphorylated cofilin to the total cofilin present. Studies in mammary tumour cells suggest that the EGF-stimulated and PLCγ-mediated hydrolysis of PIP2 can activate cofilin in mammary tumour cells 29 , and this is uncoupled from dephosphorylation 50 . In fact, during stimulation with EGF the levels of phosphorylated cofilin in mammary tumour cells increase 29,50 .…”

Section: Biochemistry Of the Cofilin Pathwaymentioning

confidence: 99%

“…Studies in mammary tumour cells suggest that the EGF-stimulated and PLCγ-mediated hydrolysis of PIP2 can activate cofilin in mammary tumour cells 29 , and this is uncoupled from dephosphorylation 50 . In fact, during stimulation with EGF the levels of phosphorylated cofilin in mammary tumour cells increase 29,50 . In this case, the release of cofilin locally from its complex with PIP2 results in its activation, at the same time as the phosphorylation of cofilin globally throughout the cell by LIMK1 leads to a net increase in phosphorylated cofilin, sharpening the cofilin activity asymmetrically inside the tumour cell (FIG.…”

Section: Biochemistry Of the Cofilin Pathwaymentioning

confidence: 99%

“…3). This early transient of barbed ends is the output of the cofilin pathway 29 and this output is positively correlated with the invasive and metastatic activity of mammary tumour cells in vivo 12,43 .…”

Section: Cell Biology Of the Cofilin Pathwaymentioning

confidence: 99%

“…In mammary tumour cells the activation and inhibition of cofilin must be balanced for transient cofilin activity to occur, be spatially localized 30 and for protrusion to occur optimally 29,30 . Too much or too little cofilin activity inhibits protrusion, chemotaxis and motility.…”

Section: Cell Biology Of the Cofilin Pathwaymentioning

confidence: 99%

“…However, how cofilin functions in cell motility and which parts of the motility cycle are affected by cofilin activity is complex and requires a careful cell-type-specific analysis. In mammary tumour cells, cofilin activity is observed to occur as a transient activity 60 seconds after stimulation of mammary tumour cells with EGF, and is responsible for the early transient of actin filament barbed end formation 29,50 (FIG. 3).…”

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The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.Tumour cell motility is the hallmark of invasion and an essential step in metastasis 1,2 . The identification of molecular pathways that contribute to tumour cell motility and invasion is essential for understanding how motility is initiated in tumour cells and how the tumour microenvironment contributes to cell migration. The identification of the molecular pathways of tumour cell invasion will provide new diagnostic approaches and targets for the treatment of metastatic cancer. Recent studies using new technologies, including highdensity microarray-based expression profiling, intravital imaging and the collection of invasive tumour cells from live tumours, have started to extend the traditional model of metastasis and supply new diagnostic and therapeutic markers of metastatic disease.According to the traditional model of metastasis, metastases result from a process similar to Darwinian evolution whereby natural selection works on individual tumour cells to select © 2007 Nature Publishing Group Correspondence to: J.C. Condeeli@aecom.yu.edu. Competing interests statementThe authors declare no competing financial interests. for stable genetic changes. The cells so selected are very rare, and the metastatic cells that arise from this progressive selection of stable genetic mutations within the primary tumour cause metastasis late in tumour progression 3 . However, studies of mammary tumours in mice [4][5][6][7] , expression profiling of both whole human breast tumours 8,9 and the invasive subpopulation of tumour cells isolated from rat and mouse mammary tumours [10][11][12] suggest that the metastatic ability of breast tumours is encoded throughout the bulk of the primary tumour, involves transient changes in gene expression and is acquired at much earlier stages of tumour progression than postulated by the traditional model. These results suggest that a Darwinian-like evolution is accompanied by, and may contribute to, microenvironmentinduced transient changes in gene expression that support the invasive and metastatic phenotype. These results have led to new models where the microenvironment initiates the expression of genes that induce cell motility, invasion and metastasis 11,13 . In the 'tumour microenvironment invasion model' it is proposed that oncogenic mutations in tumour cells lead to microenvironments that are potentially encoded throughout the b...

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Section: Biochemistry Of the Cofilin Pathwaymentioning

confidence: 99%

Section: Biochemistry Of the Cofilin Pathwaymentioning

confidence: 99%

Section: Cell Biology Of the Cofilin Pathwaymentioning

confidence: 99%

Section: Cell Biology Of the Cofilin Pathwaymentioning

confidence: 99%

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confidence: 99%

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The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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Description and characterization of a chamber for viewing and quantifying cancer cell chemotaxis

Soon

Mouneimne

Segall

et al. 2005

Cell Motil. Cytoskeleton

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Direct observations of cancer cell invasion underscore the importance of chemotaxis in invasion and metastasis. Yet, there is to date, no established method for real-time imaging of cancer chemotaxis towards factors clinically correlated with metastasis. A chamber has been designed and tested, called the Soon chamber, which allows the direct observation and quantification of cancer cell chemotaxis. The premise for the design of the Soon chamber is the incorporation of a dam, which creates a steep gradient while retaining stability associated with a pressuredriven system. The design is based on the characteristics of cancer cell motility such as relatively low speeds, and slower motility responses to stimuli compared to classical amoeboid cells like neutrophils and Dictyostelium. We tested MTLn3 breast carcinoma cells in the Soon chamber in the presence of an EGF gradient, obtaining hour-long time-lapses of chemotaxis. MTLn3 cells migrated further, more linearly, and at greater speeds within an EGF gradient compared to buffer controls. Computation of the degree of orientation towards the EGF/buffer source showed that MTLn3 cells were significantly more directional toward the EGF gradient compared to buffer controls. Analysis of the time-lapse data obtained during chemotaxis demonstrated that two populations of cancer cells were present. One population exhibited oscillations in directionality occurring at average intervals of 12 min while the second population exhibited sustained high levels of directionality toward the source of EGF. This result suggests that polarized cancer cells can avoid the need for oscillatory path corrections during chemotaxis. Cell Motil.

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N‐WASP and cortactin are involved in invadopodium‐dependent chemotaxis to EGF in breast tumor cells

DesMarais

Yamaguchi

Oser

et al. 2009

Cell Motil. Cytoskeleton

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Metastatic mammary carcinoma cells, which have previously been observed to form mature, matrix degrading invadopodia on a thick ECM matrix, are able to form invadopodia with similar characteristics on glass without previously applied matrix. They form in response to EGF, and contain the usual invadopodium core proteins N-WASP, Arp2/3, cortactin, cofilin, and F-actin. The study of invadopodia on glass allows for higher resolution analysis including the use of total internal reflection microscopy and analysis of their relationship to other cell motility events, in particular, lamellipodium extension and chemotaxis toward an EGF gradient. Invadopodium formation on glass requires N-WASP and cortactin but not microtubules. In a gradient of EGF more invadopodia form on the side of the cells facing the source of EGF. In addition, depletion of N-WASP or cortactin, which blocks invadopodium fromation, inhibits chemotaxis of cells towards EGF. This appears to be a localized defect in chemotaxis since depletion of N-WASP or cortactin via siRNA had no effect on lamellipodium protrusion or barbed end generation at the lamellipodium's leading edge. Since chemotaxis to EGF by breast tumor cells is involved in metastasis, inhibiting N-WASP activity in breast tumor cells might prevent metastasis of tumor cells while not affecting chemotaxis-dependent innate immunity which depends on WASp function in macrophages.

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Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation

Cited by 213 publications

References 56 publications

The cofilin pathway in breast cancer invasion and metastasis

The cofilin pathway in breast cancer invasion and metastasis

Description and characterization of a chamber for viewing and quantifying cancer cell chemotaxis

N‐WASP and cortactin are involved in invadopodium‐dependent chemotaxis to EGF in breast tumor cells

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