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

Muinonen-Martin, A. J. et al. (2014) Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. PLoS Biology, 12(10), e1001966. (doi:10.1371/journal.pbio.1001966) (PMID:25313567) (PMCID:PMC4196730)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Susanto, Dr Olivia and Muinonen-Martin, Dr Andrew and Faller, Dr William and Machesky, Professor Laura and Herd, Dr Robert and Lindsay, Dr Colin and Kalna, Dr Gabriela and Jones, Professor Robert and Insall, Professor Robert and Knecht, Prof David and Sansom, Professor Owen
Authors: Muinonen-Martin, A. J., Susanto, O., Zhang, Q., Smethurst, E., Faller, W. J., Veltman, D. M., Kalna, G., Lindsay, C., Bennett, D. C., Sansom, O. J., Herd, R., Jones, R., Machesky, L. M., Wakelam, M. J.O., Knecht, D. A., and Insall, R. H.
Subjects:Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN:1544-9173
ISSN (Online):1544-9173
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in PLoS Biology 12(10):e1001966
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
562761Chemotaxis in melanoma metastasis.Robert InsallWellcome Trust (WELLCOME)095186/Z/10/ZICS - BEATSON INSTITUTE FOR CANCER RES.