Monoacylglycerol lipase regulates macrophage polarization and cancer progression in uveal melanoma and pan-cancer

Abstract

BackgroundAlthough lipid metabolism has been proven to play a key role in the development of cancer, its significance in uveal melanoma (UM) has not yet been elucidated in the available literature.MethodsTo identify the expression patterns of lipid metabolism in 80 UM patients from the TCGA database, 47 genes involved in lipid metabolism were analyzed. Consensus clustering revealed two distinct molecular groups. ESTIMATE, TIMER, and ssGSEA analyses were done to identify the differences between the two subgroups in tumor microenvironment (TME) and immune state. Using Cox regression and Lasso regression analysis, a risk model based on differentially expressed genes (DEGs) was developed. To validate the expression of monoacylglycerol lipase (MGLL) and immune infiltration in diverse malignancies, a pan-cancer cohort from the UCSC database was utilized. Next, a single-cell sequencing analysis on UM patients from the GEO data was used to characterize the lipid metabolism in TME and the role of MGLL in UM. Finally, in vitro investigations were utilized to study the involvement of MGLL in UM.ResultsTwo molecular subgroups of UM patients have considerably varied survival rates. The majority of DEGs between the two subgroups were associated with immune-related pathways. Low immune scores, high tumor purity, a low number of immune infiltrating cells, and a comparatively low immunological state were associated with a more favorable prognosis. An examination of GO and KEGG data demonstrated that the risk model based on genes involved with lipid metabolism can accurately predict survival in patients with UM. It has been demonstrated that MGLL, a crucial gene in this paradigm, promotes the proliferation, invasion, and migration of UM cells. In addition, we discovered that MGLL is strongly expressed in macrophages, specifically M2 macrophages, which may play a function in the M2 polarization of macrophages and M2 macrophage activation in cancer cells.ConclusionThis study demonstrates that the risk model based on lipid metabolism may be useful for predicting the prognosis of patients with UM. By promoting macrophage M2 polarization, MGLL contributes to the evolution of malignancy in UM, suggesting that it may be a therapeutic target for UM.

Prognostic analysis of uveal melanoma based on the characteristic genes of M2-type macrophages in the tumor microenvironment

“…For monocyte chemotaxis 49 – 51 ; the regulatory pathway of pattern recognition receptor signaling pathway also indicates the chemotaxis generated by tumor cells in the body, recruiting monocyte macrophages in the immune system to further play a role in tumorigenesis development. Prior research has shown that the number and complexity of tumor trophoblast vessels can predict tumor growth rate and invasive metastasis, determining the tumor patient’s prognosis [ 52 , 53 ], M2-type macrophages have a tumor-promoting angiogenic function, and tumor-associated macrophages and their cytokines appear responsible for increased tumor aggressiveness [ 54 , 55 ]. The tumor-favorable and angiogenesis-promoting effects are directly attributable to the M2-dominated tumor microenvironment, suggesting a plausible mechanism for the tumor-promoting actions of M2-type macrophages.…”

Single cell RNA-sequencing in uveal melanoma: advances in heterogeneity, tumor microenvironment and immunotherapy

“…Wanpeng Wang et al identified the immune infiltration pattern of UM and constructed an immune-related gene prognostic signature which had strong predictive ability for UM patients (27). Similarly, Yao Tan et al investigated the expression patterns of lipid metabolism in UM patients and established a risk model based on the genes involved with lipid metabolism which could accurately predict survival in patients with UM (28). Moreover, researchers had constructed a m7Grelated prognostic signature by integrating TCGA and GEO database and suggested PAG1 as biomarker for diagnosis and treatment of UM (29).…”

“…Yao Tan et al explored the expression patterns of lipid metabolism in 80 UM patients from the TCGA database and integrated the results with single-cell sequencing analysis on UM patients from the GEO data to characterize the lipid metabolism in TME. And the results showed that monoacylglycerol lipase (MGLL) was strongly expressed in macrophages, specifically M2 macrophages, which might function in the M2 polarization and M2 macrophage activation, suggesting that MGLL might be a potential target for the immunotherapy of UM patients (28). Macrophages that recruited in TME are mostly M2 phenotype, which plays a critical role in promoting tumor progression (42).…”

Recent Advances in Molecular and Genetic Research on Uveal Melanoma

“…Pro-angiogenic tumor-associated macrophages (TAMs) within the TME are instrumental in facilitating the homing, extravasation and subsequent metastasis of UM to the liver (reviewed in [ 129 ]). Indeed, in UMs with monosomy 3, TAMs are primarily of the proangiogenic M2 polarization type [ 130 , 131 ]. RNA sequencing data from 63 UM cases has established a M2-macrophage-specific prognostic signature: CCL18, SIGLEC7, CD300LF, CAPG, LILRA4, SDS, and FAHD2CP, associated with high-risk UM groups [ 132 ].…”