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)

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 Herd, Dr Robert and Lindsay, Dr Colin and Machesky, Professor Laura and Jones, Professor Robert and Insall, Professor Robert and Knecht, Prof David and Faller, Dr William and Kalna, Dr Gabriela 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 > School 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
56276	1	Chemotaxis in melanoma metastasis.	Robert Insall	Wellcome Trust (WELLCOME)	095186/Z/10/Z	ICS - BEATSON INSTITUTE FOR CANCER RES.