Glycolysis Changes the Microenvironment and Therapeutic Response Under the Driver of Gene Mutation in Esophageal Adenocarcinoma

Abstract

Background: Esophageal cancer is one of the most leading and lethal malignancies. Glycolysis and the tumor microenvironment (TME) are responsible for cancer progressions. We aimed to study the relationships between glycolysis, TME, and therapeutic response in esophageal adenocarcinoma (EAC).Materials and Methods: We used the ESTIMATE algorithm to divide EAC patients into ESTIMATE high and ESTIMATE low groups based on the gene expression data downloaded from TCGA. Weighted gene co-expression network analysis (WGCNA) and Gene Set Enrichment Analysis (GSEA) were performed to identify different glycolytic genes in the TME between the two groups. The prognostic gene signature for overall survival (OS) was established through Cox regression analysis. Impacts of glycolytic genes on immune cells were assessed and validated. Next, we conducted the glycolytic gene mutation analysis and drug therapeutic response analysis between the two groups. Finally, the GEO database was employed to validate the impact of glycolysis on TME in patients with EAC.Results: A total of 78 EAC patients with gene expression profiles and clinical information were included for analysis. Functional enrichment results showed that the genes between ESTIMATE high and ESTIMATE low groups (N = 39, respectively) were strongly related with glycolytic and ATP/ADP metabolic pathways. Patients in the low-risk group had probabilities to survive longer than those in the high-risk group (p < 0.001). Glycolytic genes had significant impacts on the components of immune cells in TME, especially on the T-cells and dendritic cells. In the high-risk group, the most common mutant genes were TP53 and TTN, and the most frequent mutation type was missense mutation. Glycolysis significantly influenced drug sensitivity, and high tumor mutation burden (TMB) was associated with better immunotherapeutic response. GEO results confirmed that glycolysis had significant impacts on immune cell contents in TME.Conclusion: We performed a comprehensive study of glycolysis and TME and demonstrated that glycolysis could influence the microenvironment and drug therapeutic response in EAC. Evaluation of the glycolysis pattern could help identify the individualized therapeutic regime.

Development of a prognostic signature for esophageal cancer based on a novel 7-DNA damage repair genes signature

“…Inhibiting the HH pathway was linked to fewer cells with a cancer stem cellassociated phenotype (CD44+/CD24-), decreased spheroid formation, and increased radiosensitivity, according to a recent study (Wang et al, 2019). The glycolytic pathway is important in the occurrence and progression of esophageal cancer (Zhu et al, 2021). Previous research has shown that glycolysis can affect EAC immunotherapy by altering the microenvironment caused by genetic mutations (Zhu et al, 2021).…”

“…The glycolytic pathway is important in the occurrence and progression of esophageal cancer (Zhu et al, 2021). Previous research has shown that glycolysis can affect EAC immunotherapy by altering the microenvironment caused by genetic mutations (Zhu et al, 2021). CLDN9, GFPT1, HMMR, RARS, and STMN1 are glycolysis-related gene signatures that predict prognosis in patients with esophageal adenocarcinoma.…”

Enhancing cancer treatment and understanding through clustering of gene responses to categorical stressors

“…This explanation should be extended to the cancer microenvironment when translating the results of cancer responses to in vivo studies. The cancer microenvironment, which includes neighboring cells, blood vessels, and the extracellular matrix, can affect the expression of glycolysis-related genes 20 , 21 , limit drug delivery to tumor cells, and alter the immune response to the tumor 22 , 23 .…”

Enhancing Cancer Treatment and Understanding Through Clustering of Gene Responses to Categorical Stressors

“…This explanation should be extended to the cancer microenvironment when translating the results of cancer responses to in vivo studies. Thus, we should mention that the cancer microenvironment, which includes neighboring cells, blood vessels, and the extracellular matrix, can affect the expression of glycolysis-related genes 20,21 , limit drug delivery to tumor cells, and alter the immune response to the tumor 22,23 .…”