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

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 melanoma cells, and confirm the importance of attractant breakdown in LPA-mediated cell steering.This article has an associated First Person interview with the first author of the paper.

Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer

“…Interestingly, some phospholipases are secreted proteins (Park et al, 2012), suggesting that cancer cells actively modify the tumor microenvironment lipidome. Lysophospholipids produced by these secreted phospholipases can be further converted to the signaling molecule LPA by extracellular ATX/ ENPP2 (Federico et al, 2016), producing a chemotactic gradient that promotes dissemination of melanoma cells (Susanto et al, 2017). Similarly, it was recently shown that pancreatic stellate cells release lysophospholipids, which are converted to LPA by ATX/ENPP2 and promote progression in pancreatic cancer (Auciello et al, 2019).…”

N-WASP Control of LPAR1 Trafficking Establishes Response to Self-Generated LPA Gradients to Promote Pancreatic Cancer Cell Metastasis

“…Media samples were harvested every 12 h for 96 h. Prior to butanol extraction, 0.5mg of synthetic 17:0 LPA (Avanti) was added to samples. Liquid chromatography-mass spectrometry analysis was based on Susanto et al (2017). Lysophosphatidic acids (LPAs) were analyzed using a Q-Exactive Orbitrap mass spectrometer coupled to an UltiMate 3,000 LC system (Thermo Scientific).…”

CMTM8 as an LPA1-associated partner mediates lysophosphatidic acid-induced pancreatic cancer metastasis

“…Lysophosphatidic acid (LPA) is a naturally producing lipid that can modulate cell migration during development and cancer (1)(2)(3). In many cancer cell types, such as breast cancer (1), ovarian cancer (4), melanoma (5), prostate cancer (6), and pancreatic cancer (7), LPA exhibits the ability to promote migration. Besides migration, several other aspects of tumor biology including proliferation, and invasion, angiogenesis are also coordinated by LPA in restricted cancer types (8).…”