Characterization of Glycolysis-Associated Molecules in the Tumor Microenvironment Revealed by Pan-Cancer Tissues and Lung Cancer Single Cell Data

Altered metabolism is a hallmark of cancer and glycolysis is one of the important factors promoting tumor development. There is however still a lack of molecular characterization glycolysis and comprehensive studies related to tumor glycolysis in the pan-cancer landscape. Here, we applied a gene expression signature to quantify glycolysis in 9229 tumors across 25 cancer types and 7875 human lung cancer single cells and verified the robustness of signature using defined glycolysis samples from previous studies. We classified tumors and cells into glycolysis score-high and -low groups, demonstrated their prognostic associations, and identified genome and transcriptome molecular features associated with glycolysis activity. We observed that glycolysis score-high tumors were associated with worse prognosis across cancer types. High glycolysis tumors exhibited specific driver genes altered by copy number aberrations (CNAs) in most cancer types. Tricarboxylic acid (TCA) cycle, DNA replication, tumor proliferation and other cancer hallmarks were more active in glycolysis-high tumors. Glycolysis signature was strongly correlated with hypoxia signature in all 25 cancer tissues (r > 0.7) and cancer single cells (r > 0.8). In addition,HSPA8andP4HA1were screened out as the potential modulating factors to glycolysis as their expression were highly correlated with glycolysis score and glycolysis genes, which enables future efforts for therapeutic options to block the glycolysis and control tumor progression. Our study provides a comprehensive molecular-level understanding of glycolysis with a large sample data and demonstrates the hypoxia pressure, growth signals, oncogene mutation and other potential signals could activate glycolysis, thereby to regulate cell cycle, energy material synthesis, cell proliferation and cancer progression.