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CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.

ABSTRACT: Glioblastoma (GBM) is the most common primary brain tumor with a median survival under two years. Using in silico and in vitro techniques, we demonstrate heterogeneous expression of CD97, a leukocyte adhesion marker, in human GBM. Beyond its previous demonstrated role in tumor invasion, we show that CD97 is also associated with upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways in GBM. While CD97 knockout decreased Akt activation, CD97 targeting did not alter MAPK/Erk activation, did not slow GBM cell proliferation in culture, and increased levels of glycolytic and oxidative phosphorylation metabolites. Treatment with a soluble CD97 inhibitor did not alter activation of the MAPK/Erk and PI3K/Akt pathways. Tumors with high CD97 expression were associated with immune microenvironment changes including increased naïve macrophages, regulatory T cells, and resting natural killer (NK) cells. These data suggest that, while CD97 expression is associated with conflicting effects on tumor cell proliferative and metabolic pathways that overall do not affect tumor cell proliferation, CD97 exerts pro-tumoral effects on the tumor immune microenvironment, which along with the pro-invasive effects of CD97 we previously demonstrated, provides impetus to continue exploring CD97 as a therapeutic target in GBM.

SUBMITTER: Safaee MM

PROVIDER: S-EPMC8795421 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.

Safaee Michael M MM Wang Elaina J EJ Jain Saket S Chen Jia-Shu JS Gill Sabraj S Zheng Allison C AC Garcia Joseph H JH Beniwal Angad S AS Tran Y Y Nguyen Alan T AT Trieu Melissa M Leung Kevin K Wells Jim J Maclean James M JM Wycoff Keith K Aghi Manish K MK

Scientific reports 20220127 1

Glioblastoma (GBM) is the most common primary brain tumor with a median survival under two years. Using in silico and in vitro techniques, we demonstrate heterogeneous expression of CD97, a leukocyte adhesion marker, in human GBM. Beyond its previous demonstrated role in tumor invasion, we show that CD97 is also associated with upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathwa ...[more]

PMID: 35087132

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Project description:BackgroundHistidine metabolism is crucial in role in tumor biology, contributing to tumor progression, immune regulation, and metabolic reprogramming. In hepatocellular carcinoma (HCC), dysregulated histidine metabolism may promote tumor growth and immune evasion, although the specific mechanisms remain poorly understood.MethodsUsing single-cell RNA sequencing, the expression patterns of histidine metabolism-related genes were evaluated across different cell types in HCC samples. In vivo and in vitro experiments were conducted to validate how histidine treatment affects macrophage and T-cell function. Furthermore, the TCGA database was utilized to construct a prognostic model to identify the key gene BUD23 and to examine its correlation with metabolism and immune infiltration.ResultsThe proportion of parenchymal cells exhibiting high histidine metabolism was significantly increased, accompanied by a general reduction in immune and stromal cell infiltration. Notably, macrophages and T cells demonstrated impaired antitumor functions. In the high histidine metabolism group, multiple critical cell communication pathways (e.g., MIF, CLEC, MHC II) were downregulated, macrophages shifted toward immunosuppressive subpopulations, T cells exhibited an exhaustion phenotype, and CD8 + T-cell activation was diminished. Further in vivo and in vitro co-culture experiments confirmed that elevated histidine concentrations promoted M2 polarization in macrophages and weakened T-cell cytotoxicity, accelerating tumor proliferation. According to TCGA analyses, BUD23 was upregulated in the high histidine metabolism group and significantly negatively correlated with patient survival and immune cell infiltration. Silencing BUD23 boosted immune cell activation and cytotoxic effects, effectively reversing the immunosuppressive microenvironment. A multivariable Cox regression-based prognostic model indicated unfavorable outcomes in patients with high histidine metabolism.ConclusionHistidine metabolism drives tumor cell metabolic reprogramming and reshapes the tumor immune microenvironment through intercellular communication, thereby promoting tumor progression. BUD23 shows promise as a biomarker for prognosis and immune response prediction in liver cancer. This study provides new therapeutic targets and theoretical support for liver cancer treatment by targeting histidine metabolism.

Dataset Information

CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.

Publications

CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.

Similar Datasets

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