Abstract
SUMMARYIt is seldom the primary tumour that proves fatal in cancer, with metastasis the fundamental pathological process for disease progression. Upregulation of Mena, a member of the evolutionarily conserved Ena/VASP family of actin cytoskeletal regulators, promotes metastasis and invasive motility of breast cancer cells in vivo. To complement in vitro studies of Ena/VASP function in fibroblasts, we manipulated levels of Ena, the Drosophila homologue of Mena, in migrating embryonic macrophages (haemocytes). Consistent with data from fibroblasts in vitro, Ena localises to regions of actin dynamics within migrating haemocytes, stimulates lamellipodial dynamics and positively regulates the number and length of filopodia. However, whereas Ena overexpression in fibroblasts reduces migration speeds, overexpressing Ena in haemocytes leads to a dramatic increase in migration speeds, more closely resembling the increased motility of breast cancer cells that overexpress Mena. We provide evidence that this key difference is due to spatial constraints imposed on cells within the three-dimensional environment of the embryo; this might explain how Mena can be used to promote aggressive migratory behaviour during cancer progression.
Highlights
The metastasis of cancer cells from the primary tumour is the key step in cancer progression and requires invasive cell migration, a process important during development (Hanahan and Weinberg, 2000; Franz et al, 2002)
Despite stimulating protrusion and lamellipodial dynamics in a similar fashion to that seen in fibroblasts, we find that Ena overexpression increases haemocyte migration speed, resembling the effect of Mena overexpression in cancer cells in vivo
Ena itself is widely expressed within Drosophila embryos; levels are high within the central nervous system (CNS) (Gertler et al, 1995) and the protein is present within haemocytes
Summary
The metastasis of cancer cells from the primary tumour is the key step in cancer progression and requires invasive cell migration, a process important during development (Hanahan and Weinberg, 2000; Franz et al, 2002). Actin polymerisation drives the formation of protrusions at the leading edge of a migrating cell, and adhesion of protrusions coupled with retraction and disassembly of adhesions at the rear of the cell enable continued migration. Actin filaments are organised into broad, sheet-like lamellipodia, which consist of branched arrays of filaments at the leading edge, or are bundled into finger-like filopodial protrusions (Pollard and Borisy, 2003; Ridley et al, 2003). One actin-regulatory protein recently implicated in several human cancers is Mena (Di Modugno et al, 2004; Toyoda et al, 2009), a member of the Ena/VASP family (Drosophila Enabled, vasodilator-stimulated phosphoprotein) (Gertler et al, 1996), which antagonise capping of barbed ends of actin filaments, facilitating their continued elongation and stimulating cell protrusion (Bear et al, 2002). Ena/VASP proteins are targeted downstream of numerous guidance receptors (Bashaw et al, 2000; Evans et al, 2007; Lebrand et al, 2004), with the misregulation of many of these implicated in cancer
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