PDF(Pubmed)
Abstract：
Lysophosphatidic acid (LPA) species, prevalent in the tumor microenvironment (TME), adversely impact various cancers. In ovarian cancer, the 18:0 and 20:4 LPA species are selectively associated with shorter relapse-free survival, indicating distinct effects on cellular signaling networks. Macrophages represent a cell type of high relevance in the TME, but the impact of LPA on these cells remains obscure. Here, we uncovered distinct LPA-species-specific responses in human monocyte-derived macrophages through unbiased phosphoproteomics, with 87 and 161 phosphosites upregulated by 20:4 and 18:0 LPA, respectively, and only 24 shared sites. Specificity was even more pronounced for downregulated phosphosites (163 versus 5 sites). Considering the high levels 20:4 LPA in the TME and its selective association with poor survival, this finding may hold significant implications. Pathway analysis pinpointed RHO/RAC1 GTPase signaling as the predominantly impacted target, including AHRGEF and DOCK guanine exchange factors, ARHGAP GTPase activating proteins, and regulatory protein kinases. Consistent with these findings, exposure to 20:4 resulted in strong alterations to the actin filament network and a consequent enhancement of macrophage migration. Moreover, 20:4 LPA induced p38 phosphorylation, a response not mirrored by 18:0 LPA, whereas the pattern for AKT was reversed. Furthermore, RNA profiling identified genes involved in cholesterol/lipid metabolism as selective targets of 20:4 LPA. These findings imply that the two LPA species cooperatively regulate different pathways to support functions essential for pro-tumorigenic macrophages within the TME. These include cellular survival via AKT activation and migration through RHO/RAC1 and p38 signaling.
摘要：
溶血磷脂酸（LPA）物种，在肿瘤微环境(TME)中普遍存在，对各种癌症产生不利影响。在卵巢癌中，18:0和20:4LPA物种选择性地与较短的无复发生存期相关，表明对蜂窝信令网络的不同影响。巨噬细胞代表TME中高度相关的细胞类型，但是LPA对这些细胞的影响仍然不清楚。这里,我们通过无偏倚的磷酸化蛋白质组学发现了人类单核细胞衍生的巨噬细胞中不同的LPA物种特异性反应，87和161个磷酸位点上调20:4和18:0LPA，分别,只有24个共享网站。对于下调的磷酸位点(163对5个位点),特异性甚至更显著。考虑到TME中高水平的20:4LPA及其与低生存率的选择性关联，这一发现可能会产生重大影响。路径分析确定RHO/RAC1GTP酶信号传导为主要受影响的靶标，包括AHRGEF和DOCK鸟嘌呤交换因子，ARHGAPGTPase激活蛋白,和调节蛋白激酶。与这些发现一致，暴露于20：4导致肌动蛋白丝网络的强烈改变，并因此增强了巨噬细胞的迁移。此外，20:4LPA诱导p38磷酸化,18:0LPA未反映的响应，而AKT的模式逆转。此外，RNA谱分析将参与胆固醇/脂质代谢的基因鉴定为20:4LPA的选择性靶标。这些发现暗示两种LPA物种协同调节不同的途径以支持TME内的促肿瘤性巨噬细胞所必需的功能。这些包括通过AKT激活的细胞存活和通过RHO/RAC1和p38信号传导的迁移。
