B7-H3 interaction with cMet enhances lipolysis to drive malignant progression of glioma via pSTAT3-ATGL axis

Although metabolic dysregulation serves as a pivotal hallmark in glioma, the detailed information about the lipid metabolism regulation is largely unknown. In the context of this investigation, we have identified B7-H3 — an immune checkpoint molecule of the B7 family — as a regulator of lipid metabolism in glioma. A series of enrichment analyses were applied to explore the interaction between metabolic reprogramming and prognosis in glioma. The expression and prognostic value of B7-H3 were detected in both public databases and clinical samples. Furthermore, the effect of B7-H3 on Glioma cells malignance and lipid metabolism was evaluated through in vivo and in vitro functional experiments. Finally, the molecular mechanism of B7-H3 was investigated by the study of transcriptome sequencing and key interacting proteins. The metabolism associated genes (MAG) were firstly screened from the prognosis related differentially expressed genes (DEG) using the TCGA and verified CGGA derived primary and recurrent cohorts of glioma patients, and the immune checkpoint molecule CD276 (B7-H3) was selected due its significant poor prognosis correlation in both primary and recurrent glioma. Furthermore, both RNA sequencing and untargeted metabolomics profiling confirmed a strong correlation between B7-H3 and lipid metabolism in glioma. Notably, B7-H3 showed a significant positive correlation with lipolytic enzyme ATGL (PNPLA2) according to the above transcriptomic data and CGGA database of glioma. However, the receptors of B7-H3 on cancer cells remained poorly understood. Here, we reported that B7-H3 modulated abnormal lipolysis during glioma progression by forming a complex with cMet, and subsequent simultaneous promoting the phosphorylation of STAT3 and expression of ATGL. More importantly, B7-H3 protein level was associated with poor prognosis and correlated with ATGL status in glioma. Our results define B7-H3 as a lipolysis related factor that acts by driving glioma malignancy via the cMet-pSTAT3-ATGL pathway, thereby nominating both B7-H3 and ATGL as potential therapeutic targets for glioma.