title: Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.
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.
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom; York Teaching Hospital NHS Foundation Trust, York, United Kingdom; The Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muinonen-Martin
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Olivia
authors.initials: O
authors.lastname: Susanto
authors.affiliation: The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smethurst
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: William J
authors.initials: WJ
authors.lastname: Faller
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Douwe M
authors.initials: DM
authors.lastname: Veltman
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Lindsay
authors.affiliation: Molecular Cell Sciences Research Centre, St. George's, University of London, London, United Kingdom.
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Alan Lyell Centre for Dermatology, Glasgow, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Herd
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Jones
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Machesky
authors.affiliation: The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Michael J O
authors.initials: MJ
authors.lastname: Wakelam
authors.affiliation: Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Knecht
authors.affiliation: CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Insall
mesh_terms: D000818:Animals; D002465:Cell Movement; D002633:Chemotaxis; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008246:Lysophospholipids; C032881:lysophosphatidic acid