Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal

Abstract

Melanoma cells break down lysophosphatidic acid from the environment, creating a chemotactic gradient that the tumor cells then follow; this provides an explanation for the rapid metastasis of melanoma.

Exosome secretion promotes chemotaxis of cancer cells

“…22,23 Chemotaxis of cancer cells is thought to promote cancer metastasis. [24][25][26][27][28] For example, melanoma cells are directed out from tumors toward a higher level of a chemoattractant, lysophosphatidic acid, to intravasate into local blood vessels. 26 Another example is metastasis of breast cancer cells to the lung, driven by SDF-1 and its receptor CXC chemokine receptor 4 (CXCR4).…”

“…[24][25][26][27][28] For example, melanoma cells are directed out from tumors toward a higher level of a chemoattractant, lysophosphatidic acid, to intravasate into local blood vessels. 26 Another example is metastasis of breast cancer cells to the lung, driven by SDF-1 and its receptor CXC chemokine receptor 4 (CXCR4). [27][28][29] Recently, exosome secretion was shown to enhance chemotaxis of neutrophils and macrophages.…”

Exosomes bind to autotaxin and act as a physiological delivery mechanism to stimulate LPA receptor signalling in cells

“…The physiological importance of this reaction is emphasised by the embryonic lethality associated with the mouse Atx knockout (van Meeteren et al, 2006). The lipid product of ATX activity, LPA, binds to members of a family of cell surface G-protein-coupled seventransmembrane receptors and thereby stimulates a number of signalling pathways (including those comprising phosphoinositide 3-kinase, ras, phospholipase C and phospholipase D, and Rho) that activate physiological responses such as proliferation, migration, development or contraction, as well as those protecting against apoptosis, depending upon cell type (Houben and Moolenaar, 2011;Muinonen-Martin et al, 2014).…”

Collective cell migration in development

“…Although recent work has highlighted a role for cadherin-dependent mechanical feedback in promoting polarized protrusion formation in diverse models such as border cells (Cai et al, 2014), Xenopus mesendoderm (Weber et al, 2012), and neural crest (Scarpa et al, 2015), the molecular mechanisms linking stress-sensing at the cell-cell adhesion to control of distant lamellipodial activity are not yet completely clear. In vivo observations suggest that similar mechanisms may be hijacked in tumor collective invasion (Astin et al, 2010;Muinonen-Martin et al, 2014), and developmental models of collective migration are likely to provide useful insights.…”

“…Collectively, these works highlight how cell collectives use different strategies to respond to cues located in their surroundings and how differential expression of surface molecules within the collective itself is exploited to promote a local response to chemoattractants. Interestingly, self-generated chemokine gradients have recently been found to promote migration of invasive melanoma cells (Muinonen-Martin et al, 2014), which highlights how collectively migrating cancer cells might deploy similar tactics. The SDF-1 receptor Cxcr7 is expressed at the back of the group, whereas Cxcr4 is expressed at the front and the back.…”