The cofilin pathway in breast cancer invasion and metastasis

Abstract

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...

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

“…Actin cytoskeleton participates in many cellular processes, including muscle contraction, cell motility and cell signaling. Cofilin 1 has a pivotal role in actin dynamics by modulating actin polymerization and depolymerization through its severing activity [33][34][35]. Here we find that depletion of NudC causes an accumulation of bundled stress fibers and inhibits cell spreading and lamellipodia formation (Figure 1), resembling the cellular phenotypes induced by cofilin 1 knockdown [29,30,33].…”

“…Cofilin 1 has a pivotal role in actin dynamics by modulating actin polymerization and depolymerization through its severing activity [33][34][35]. Here we find that depletion of NudC causes an accumulation of bundled stress fibers and inhibits cell spreading and lamellipodia formation (Figure 1), resembling the cellular phenotypes induced by cofilin 1 knockdown [29,30,33]. Furthermore, our results show that NudC forms a complex with cofilin 1, colocalizes with cofilin 1 especially at the leading edge and influences the stability of cofilin 1 ( Figure 4).…”

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

“…A more recent study, also in human aortic endothelial cells, revealed that Ang-(1–7) stimulated cofilin-1 expression [48]. Cofilin-1 is known to be involved in regulating actin filament dynamics and in cytokinesis [49] and has previously been implicated in cancer progression [50]. Ang-(1–7) stimulated G0/G1 arrest through a pathway involving cofilin 1, suggesting its importance for maintaining cell cycle homeostasis in response to Ang-(1–7) [48].…”

MTSS1 is a metastasis driver in a subset of human melanomas

“…Unphosphorylated active cofilin associates with actin filaments in cell membrane protrusions where it drives actin dynamics by depolymerizing and severing ADP-bound actin filaments to regenerate the pool of In vivo metastasis 3/9 (33%) 7/9 (78%) actin monomers for new rounds of assembly at filament barbed ends 43 . Furthermore, the severing activity of cofilin is important for generation of the branched actin filament network that drives invasion and metastasis of cancer cells 44 .…”