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Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

Muinonen-Martin, AJ; Susanto, O; Zhang, Q; Smethurst, E; Faller, WJ; Veltman, DM; Kalna, G; Lindsay, C; Bennett, DC; Sansom, OJ; et al. Muinonen-Martin, AJ; Susanto, O; Zhang, Q; Smethurst, E; Faller, WJ; Veltman, DM; Kalna, G; Lindsay, C; Bennett, DC; Sansom, OJ; Herd, R; Jones, R; Machesky, LM; Wakelam, MJ; Knecht, DA; Insall, RH (2014) Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. PLoS Biology, 12 (10). ISSN 1545-7885 https://doi.org/10.1371/journal.pbio.1001966
SGUL Authors: Bennett, Dorothy Catherine

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Abstract

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient.

Item Type: Article
Additional Information: ©2014 Muinonen-Martin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Developmental Biology, 06 Biological Sciences, 11 Medical And Health Sciences, 07 Agricultural And Veterinary Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: PLoS Biology
Article Number: e1001966
ISSN: 1545-7885
Language: eng
Dates:
DateEvent
14 October 2014Published
PubMed ID: 25313567
Web of Science ID: WOS:000344461700005
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107278
Publisher's version: https://doi.org/10.1371/journal.pbio.1001966

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