Autotaxin and LPA₁ and LPA₅ receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis

Autotaxin (ENPP2/ATX) and lysophosphatidic acid (LPA) receptors represent two key players in regulating cancer progression. The present study sought to understand the mechanistic role of LPA G protein-coupled receptors (GPCR), not only in the tumor cells but also in stromal cells of the tumor microenvironment. B16F10 melanoma cells predominantly express LPA₅ and LPA₂ receptors but lack LPA₁ LPA dose dependently inhibited invasion of cells across a Matrigel layer. RNAi-mediated knockdown of LPA₅ relieved the inhibitory effect of LPA on invasion without affecting basal invasion. This suggests that LPA₅ exerts an anti-invasive action in melanoma cells in response to LPA. In addition, both siRNA-mediated knockdown and pharmacologic inhibition of LPA₂ reduced the basal rate invasion. Unexpectedly, when probing the role of this GPCR in host tissues, it was found that the incidence of melanoma-derived lung metastasis was greatly reduced in LPA₅ knockout (KO) mice compared with wild-type (WT) mice. LPA₁-KO but not LPA₂-KO mice also showed diminished melanoma-derived lung metastasis, suggesting that host LPA₁ and LPA₅ receptors play critical roles in the seeding of metastasis. The decrease in tumor cell residence in the lungs of LPA₁-KO and LPA₅-KO animals was apparent 24 hours after injection. However, KO of LPA₁, LPA₂, or LPA₅ did not affect the subcutaneous growth of melanoma tumors. Implications: These findings suggest that tumor and stromal LPA receptors, in particular LPA₁ and LPA₅, play different roles in invasion and the seeding of metastasis.