Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers

Abstract

SUMMARY Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.

Metabolic deregulation in prostate cancer

“…In all, 20 pathways were assessed (Table S1). These pathways were assembled from the curated lists by Peng et al (2018) [13], Fabregat et al (2016) [14], our previous comprehensive curation of pathways [17], and from KEGG [15] via the InnateDB platform (http://www.innatedb.com/) [16].…”

“…Metabolism pathways I -Clustering of PCa patients and initial analysis of pathways was performed using genes from amino acid metabolism (348), carbohydrate metabolism (286), lipid metabolism (766), tricarboxylic acid cycle (TCA cycle, 148), and vitamin & cofactor metabolism (168) pathways, the five main pathways listed in Peng et al [13].…”

Caspase recruitment domain family member 10 regulates carbamoyl phosphate synthase 1 and promotes cancer growth in bladder cancer cells

“…The main intrinsic factors that promote tumour growth usually contribute to abnormal expression of cell cycle-related proteins or metabolic genes in bladder cancer. 22,23 Therefore, we performed metabolic MS and RNA sequencing to identify the metabolic and molecular features of CARD10. The metabolomics data indicated that CARD10 mainly affects urea metabolism, especially nitrogen metabolism.…”

The immunological Warburg effect: Can a metabolic‐tumor‐stroma score (MeTS) guide cancer immunotherapy?

“…Master regulators of carbohydrate and nucleotide metabolism showed consistently poor prognostic patterns across all analyzed cancer types whereas lipid metabolism showed the opposite association. 81 Accordingly, the expression of enzymes and transporters involved in glucose metabolism has been linked to unfavorable patient outcome in different tumor entities such as hepatocellular carcinoma, 82,83 melanoma 84,85 or urothelial carcinoma. 86 Moreover, in oral squamous cell carcinoma a high PET signal, thus a high glucose uptake, correlates with worse prognosis 83 and similarly, high intra-tumoral lactate concentration predicts the occurrence of metastases and patient survival.…”