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Characterization of Heterogeneous Metabolism in Hepatocellular Carcinoma Identifies New Therapeutic Target and Treatment Strategy
44 Pages Posted: 25 Jun 2020
More...Abstract
Background: Metabolic reprogramming is a well-known hallmark of cancer. Systematical identification of clinically relevant metabolic subtypes of Hepatocellular carcinoma (HCC) is critical to understand tumor heterogeneity and develop efficient treatment strategies.
Methods: We performed an integrative analysis of genomic, transcriptomic, and clinical data from an HCC patient cohort in The Cancer Genome Atlas (TCGA). In vitro experiments were carried out for preliminary validation.
Findings: Four metabolic subtypes were defined: mHCC1, mHHC2, mHCC3, and mHCC4. These subtypes had distinct differences in mutations profiles, activities of metabolic pathways, prognostic metabolism genes, and immune features. The mHCC1 was associated with poorest outcome and was characterized by extensive metabolic alterations, abundant immune infiltration, and increased expression of immunosuppressive checkpoints. The mHHC2 displayed lowest metabolic alteration level and was associated with most significant improvement in overall survival in response to high CD8+ T cell infiltration. The mHHC3 was a “cold-tumor” with low immune infiltration and few metabolic alterations. The mHCC4 presented a medium degree of metabolic alteration and high CTNNB1 mutation rate. Based on our HCC classification and in vitro study, we identified palmitoyl-protein thioesterase 1 (PPT1) was a specific prognostic gene and therapeutic target for mHCC1.
Interpretation: Our study highlighted mechanistic differences among metabolic subtypes and identified potential therapeutic targets for subtype-specific treatment strategies targeting unique metabolic vulnerabilities. The immune heterogeneities across metabolic subtypes may help further clarify the association between metabolism and immune environment, and guide the development of novel strategies through targeting both unique metabolic vulnerabilities and immunosuppressive triggers.
Funding Statement: This work was financially supported by the Outstanding Youth Scholars Project of Guangdong Provincial People's Hospital (No. KJ012019096).
Declaration of Interests: All financial interests are unrelated to this study. All authors declare no competing interests.
Keywords: Hepatocellular carcinoma, metabolism, differential gene expression, personalized treatment
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