Targeting lipid metabolism of macrophages: A new strategy for tumor therapy

Shao, Nan; Qiu, Hui; Liu, Jing; Xiao, Daimin; Zhao, Juanjuan; Chen, Chao; Wan, Jiajia; Guo, Mengmeng; Liang, Guiyou; Zhao, Xu; Xu, Lin

doi:10.1016/j.jare.2024.02.009

Cited by 10 publications

(1 citation statement)

References 93 publications

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“…Lipid metabolic reprogramming, encompassing processes such as fatty acid uptake, intracellular storage, catabolism, as well as altered cholesterol metabolism, significantly influences the polarization of TAMs, consequently impacting tumor progression [54]. Notably, the promotion of pro-tumorigenic TAM polarization is correlated with cholesterol depletion, primarily stemming from reduced cholesterol biosynthesis and enhanced efflux [55,56].…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomics Reveals Selective Regulation of Signaling Pathways by Lysophosphatidic Acid Species in Macrophages

Dietze,

Szymanski,

Ojasalu

et al. 2024

Cells

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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.

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Section: Discussionmentioning

confidence: 99%