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

TLDR

Metabolic reprogramming is a key source of clinical information in oncology. The study classifies metabolic expression subtypes across 33 cancer types to uncover prognostic patterns, master regulators, and drug sensitivity. Using 9,125 TCGA samples, tumors were clustered by mRNA expression of seven metabolic processes to define subtypes and evaluate their clinical relevance. The subtypes strongly predict outcomes—carbohydrate, nucleotide, and vitamin/cofactor‑upregulated subtypes associate with poorer survival, lipid‑upregulated subtypes with better prognosis—and link to oncogenic drivers, master regulators, and drug sensitivities, as shown by SNAI1/RUNX1 knockdown experiments.

Abstract

Highlights•Classification of metabolic expression subtypes in 33 TCGA cancer types•Metabolic expression subtypes show consistent prognostic patterns across cancer types•Analysis of master regulators of metabolic subtypes suggesting therapeutic targets•Metabolic expression subtypes associated with sensitivity to drugs in clinical useSummaryMetabolic 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.Graphical abstract