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

Olivia Susanto, Yvette W.H. Koh, Nick Morrice, Sergey Tumanov, Peter A. Thomason, Matthew Nielson, Luke Tweedy, Andrew J. Muinonen-Martin, Jurre J. Kamphorst, Gillian M. Mackay, Robert H. Insall

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16 Citations (Scopus)

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 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 of 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 the ability of melanoma cells to invade. Our results demonstrate that LPP3 is the key enzyme in the breakdown of LPA by melanomacells, and confirmthe importance of attractant breakdown in LPA-mediated cell steering.

Original languageEnglish
Pages (from-to)3455-3466
Number of pages12
JournalJournal of Cell Science
Volume130
Issue number20
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Keywords

  • Chemotaxis
  • LPA
  • LPP3
  • Melanoma
  • Metastasis
  • Self-generated gradients

Cite this

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., & Insall, R. H. (2017). LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells. Journal of Cell Science, 130(20), 3455-3466. https://doi.org/10.1242/jcs.207514