Abstract
BackgroundGenerally, cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. However, the mutual relationship between two critical metabolic pathways, glycolysis and oxidative phosphorylation (OXPHOS), remains poorly defined.MethodsWe developed a “double-score” system to quantify glycolysis and OXPHOS in 9668 patients across 33 tumor types from The Cancer Genome Atlas and classified them into four metabolic subtypes. Multi-omics bioinformatical analyses was conducted to detect metabolism-related molecular features.ResultsCompared with patients with low glycolysis and high OXPHOS (LGHO), those with high glycolysis and low OXPHOS (HGLO) were consistently associated with worse prognosis. We identified common dysregulated molecular features between different metabolic subgroups across multiple cancers, including gene, miRNA, transcription factor, methylation, and somatic alteration, as well as investigated their mutual interfering relationships.ConclusionOverall, this work provides a comprehensive atlas of metabolic heterogeneity on a pan-cancer scale and identified several potential drivers of metabolic rewiring, suggesting corresponding prognostic and therapeutic utility.
Highlights
Cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation
In terms of Glycolysis score, the median was − 0.30 (− 0.33 to − 0.24) for lymphoid neoplasm diffuse large B-cell lymphoma (DLBC); for acute myeloid leukemia (LAML), the value was even lower: − 0.35 (− 0.39 to − 0.31). These were in contrast to the solid tumor types such as colon adenocarcinoma (COAD): 0.17 (0.08–0.27), liver hepatocellular carcinoma (LIHC): 0.014 (0.08–0.21), and rectum adenocarcinoma (READ): 0.14 (0.07–0.24). These results suggest that glycolysis-related genes are significantly upregulated in digestive malignancies such as COAD, LIHC, and READ, leading to the increased score, while the Glycolysis scores are much lower in non-solid tumors like DLBC and LAML
We found that HIF1A, which is up-regulated in 15 tumor types as mentioned above, served as a master transcription factor (TF) for the high glycolysis and low OXPHOS (HGLO) phenotype in 7 of them, as tumor formation associated gene SNAPC1 was identified as its downstream target in 6 cancers [41]
Summary
Cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. The mutual relationship between two critical metabolic pathways, glycolysis and oxidative phosphorylation (OXPHOS), remains poorly defined. The key characteristic of tumor metabolism is the phenomenon that instead of oxidative phosphorylation (OXPHOS), cancer cells prefer to enhance glucose uptake and rely on aerobic glycolysis, even in the presence of oxygen and fully functioning mitochondria, known as Warburg effect [2,3,4]. By employing multi-omics molecular data from The Cancer Genome Atlas (TCGA) across 33 cancer types, we stratified patients into different subgroups based on the expression patterns of glycolytic and OXPHOS genes, and explore their survival status and key-regulators potentially driving metabolic alteration from multiple dimensions
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