Chemotaxis is the migration of cells in response to a gradient of attractants and is also thought to contribute to the metastasis of highly invasive cancers such as melanoma. Robert Insall's group previously reported that the phospholipid signalling molecule lysophosphatidic acid (LPA) is a strong chemoattractant for melanoma cells and establishes a self-generating gradient, with a low LPA concentration within the tumour and high LPA on the outside. On page 3455, Olivia Susanto and colleagues now build on this earlier work and investigate in more detail the mechanisms by which melanoma cells break down LPA, focusing on the role of lipid phosphate phosphatase 3 (LPP3). To that end, they first develop a robust chemotactic assay for self-generated chemotaxis. The authors then use this to show that knockdown of LPP3 reduces the ability of melanoma cells to break down LPA molecules that are chemotactically active, such as the 18:1 and 20:4 species, and leads to a delay in cell migration. This confirms that LPP3 is indeed the key enzyme for LPA degradation and that its breakdown is responsible for chemotaxis, as inhibition of de novo LPA synthesis had no effect. Furthermore, the authors also demonstrate the importance of LPA gradients for invasion in a 3D setting. Taken together, these data provide clear evidence for the role of LPA degradation in steering melanoma cells; this might also be relevant for future therapeutic strategies against invasive cancers.
