Uncovering unique roles of LPA receptors in the tumor microenvironment

The role of the lysophospholipase D autotaxin (ATX) and lysophosphatidic acid (LPA) in cancer is emerging and represents two key players in regulating cancer progression. In this brief review, we will discuss some of our recent findings, which highlight a central role that LPA and its receptor plays in orchestrating melanoma-stroma interactions in the establishment of lung metastases. In particular, we evaluated not only the function of LPA receptors on tumor cells but also their role on host tissues and how they can influence melanoma growth and metastasis. Using the syngeneic B16F10 murine melanoma model, we made three key observations. First, our in vitro findings demonstrate that LPA receptors, specifically LPA₂ and LPA₅ expressed in B16F10 cells appear to have opposing roles in cell invasion; the former seems to be responsible for the high basal invasion rate of B16F10 cells while the latter is anti-invasive upon exogenous LPA stimulation. Second, we observed a profound reduction in the incidence of pulmonary melanoma metastasis in LPA₁- and LPA₅-knockout (KO) mice, respectively, when compared to wild-type (WT) mice. Third, no differences in terms of subcutaneous tumor growth between LPA₁KO, LPA₅KO and WT mice were observed. These findings suggest that LPA receptors exert different functions in melanoma cells versus host tissues in terms of invasion and metastasis.