Ruoyu Huang

Patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patients is crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3 and PKM2 enhances the latter’s tetramerization and promotes lactate accumulation in glioblastoma stem cells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin α, allowing for greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening of a small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show that ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.

Background: Researches on immunotherapy of glioma has been increasing exponentially in recent years. However, autoimmune-like side effects of current immune checkpoint blockade hindered the clinical application of immunotherapy in glioma. The discovery of the TIM-3, a tumor-specific immune checkpoint, has shed a new light on solution of this dilemma. We aimed at investigating the role of TIM-3 at transcriptome level and its relationship with clinical practice in glioma.Methods: A cohort of 325 glioma patients with RNA-seq data from Chinese Glioma Genome Atlas (CGGA project) was analyzed, and the results were well validated in TCGA RNA-seq data of 699 gliomas. R language was used as the main tool for statistical analysis and graphical work.Results: TIM-3 was enriched in glioblastoma (the most malignant glioma) and IDH-wildtype glioma. TIM-3 can act as a potential marker for mesenchymal molecular subtype according to TCGA transcriptional classification scheme in glioma. TIM-3 was closely related to immune functions in glioma, especially T cell mediated immune response to tumor cell and T cell mediated cytotoxicity directed against tumor cell target. Moreover, TIM-3 and PD-L1 played almost exactly the same inflammatory activation functions in glioma. Clinically, high expression of TIM-3 was an independent indicator of poor prognosis.Conclusion: The expression of TIM-3 is closely related to the pathology and molecular pathology of glioma. Meanwhile, in glioma TIM-3 plays a specific role in T cell tumor immune response. Therefore, TIM-3 is a promising target for immunotherapeutic strategies, providing an alternative treatment when glioma gains resistance to antibodies of PD-1/PD-L1.

Now, numerous exciting findings have been yielded in the field of energy metabolism within glioma cells. In addition to aerobic glycolysis, multiple catabolic pathways are employed for energy production. However, the prognostic significance of energy metabolism in glioma remains obscure. Here, we explored the relationship between energy metabolism gene profile and outcome of diffuse glioma patients using The Cancer Genome Altas (TCGA) and Chinese Glioma Genome Altas (CGGA) datasets. Based on the gene expression profile, consensus clustering identified two robust clusters of glioma patients with distinguished prognostic and molecular features. With the Cox proportional hazards model with elastic net penalty, an energy metabolism-related signature was built to evaluate patients’ prognosis. Kaplan-Meier analysis found that the acquired signature could differentiate the outcome of low and high-risk groups of patients in both cohorts. Moreover, the signature, significantly associated with the clinical and molecular features, could serve as an independent prognostic factor for glioma patients. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) showed that gene sets correlated with high-risk group were involved in immune and inflammatory response, with the low-risk group were mainly related to glutamate receptor signaling pathway. Our results provided new insight into energy metabolism role in diffuse glioma.