LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells

Susanto, O. et al. (2017) LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells. Journal of Cell Science, 130(20), pp. 3455-3466. (doi: 10.1242/jcs.207514) (PMID:28871044) (PMCID:PMC5665449)

Abstract

Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then also migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency. Knockdown of the lipid phosphatase LPP3 - but not its homologues LPP1 or LPP2 - diminishes the cell's ability to break down LPA. This is specific for chemotactically active LPAs, such as the 18:1 and 20:4 species. Inhibition of autotaxin-mediated LPA production does not diminish outward chemotaxis, but loss of LPP3-mediated LPA breakdown blocks it. Similarly, in both 2D and 3D invasion assays, knockdown of LPP3 diminishes melanoma cells' ability to invade. Our results demonstrate that LPP3 is the key enzyme in melanoma cells' breakdown of LPA, and confirm the importance of attractant breakdown in LPA-mediated cell steering.

• Item Type: Articles
• Additional Information: We are grateful to Dorothy Bennett, Elena Sviderskaya and the Wellcome Trust Functional Genomics Cell Bank for melanoma cells lines, Heather Spence, Ben Tyrrell and Niels van der Broek for technical help, Laura Machesky and Clelia Amato for helpful comments on the manuscript, BAIR for microscopy support and CRUK (grants A20017 and A15672) for funding.
• Keywords: Chemotaxis, LPA, LPP3, melanoma, metastasis, self-generated gradients.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Muinonen-Martin, Dr Andrew and Susanto, Dr Olivia and Kamphorst, Dr Jurre and Thomason, Dr Peter and Tumanov, Dr Sergey and Insall, Professor Robert and Mackay, Dr Gillian and Morrice, Dr Nicholas
• Authors: Susanto, O., Koh, Y. W.H., Morrice, N., Tumanov, S., Thomason, P. A., Nielson, M., Tweedy, L., Muinonen-Martin, A. J., Kamphorst, J. J., Mackay, G. M., and Insall, R. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Cell Science
• Publisher: Company of Biologists
• ISSN: 0021-9533
• ISSN (Online): 1477-9137
• Published Online: 22 September 2017
• Copyright Holders: Copyright © 2017 The Company of Biologists Ltd
• First Published: First published in Journal of Cell Science 130(20): 3455-3466
• Publisher Policy: Reproduced under a Creative Commons license