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

BACKGROUND: Although 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. METHODS: To 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. RESULTS: Two 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. CONCLUSION: This 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.