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.

Comprehensive analysis of ADGRE5 gene in human tumors: Clinical relevance, prognostic implications, and potential for personalized immunotherapy

“…The results showed that in the LGG, ADGRE5 was significantly positively correlated with NK CD56dim cells, T cells, macrophages, neutrophils, eosinophils, cytotoxic cells, aDC, Th17 cells, iDC, Th2 cells, DC, T helper cells, B cells, Th1 cells, and mast cells and negatively correlated with pDC and Tcm. This is consistent with the results of Safaee et al, who found that the expression of non-polarized M0 macrophages, immunosuppressive Treg cells, and resting NK cells increased in glioma cells with high ADGRE5 expression [ 37 ]. Under UVM, ADGRE5 was significantly positively correlated with Th2 cells, aDC, Th1 cells, eosinophils, TFH, NK CD56dim cells, Tgd, T cells, cytotoxic cells, macrophages, T helper cells, neutrophils, DC, B cells, and iDC and negatively correlated with Th17 cells and pDC.…”

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

“…In addition to the MAPK signaling pathway, past research on CD97 has identified other signaling mechanisms, including G protein-mediated Gα i (reduces cyclic-AMP) and Gα 12/13 (activates RHOA) activation and PI3K/AKT pathway activation ( Figure 5A ). 27 , 31 , 51 , 52 We investigated whether CD97 influenced these other signaling pathways in our PDGCs. CD97 overexpression in our PDGCs did not alter canonical G protein-mediated signaling as measured by luciferase reporter assays ( Figure S4B ).…”

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

“…In addition to the MAPK signaling pathway, past research on CD97 has identified other signaling mechanisms, including G protein-mediated Gα i (reduces cyclic-AMP) and Gα 12/13 (activates RHOA) activation, and PI3K/AKT pathway activation ( Figure 5A ). 27,31,51,52 We investigated whether CD97 influenced these other signaling pathways in our PDGCs. CD97 overexpression in our PDGCs did not alter canonical G protein-mediated signaling as measured by luciferase reporter assays ( Supp.…”

“…[25][26][27][28] CD97 expression in GBM was first demonstrated in 2012, when it was found to confer a migratory phenotype. 33 More recent work has also implicated CD97 in cellular proliferation, GBM stem cell self-renewal, and tumor metabolism, [29][30][31][32] but the underlying mechanisms have not been elucidated. Here, we have taken a methodical approach to characterize the oncogenic function of CD97 in GBM using PDGCs from all TCGA-defined transcriptional subtypes (proneural, classical, mesenchymal) and advanced genetic, transcriptomic, metabolomic, cellular, and biochemical approaches.…”

“…The synthesis of our experimental data led us to formulate the hypothesis that CD97's effects on GBM cellular metabolism and tumor growth are driven by its activation of the MAPK/ERK pathway. 31,51 This pathway has been implicated in a slew of cellular functions, including cellular metabolism, proliferation, and migration. 65 From the metabolism point of view, MAPK signaling modulates several enzymes involved in glycolytic and TCA cycle/OXPHOS pathways.…”