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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Glycine decarboxylase is a metabolic oncogene critical for tumor initiating cells and tumorigenesis in lung cancer

ABSTRACT: New approaches to cancer therapies could benefit from a better understanding of the molecular determinants critical to tumor initiating cells (TICs). Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). From a broad range of primary NSCLC tumors, we isolated CD166+ lung TICs that consistently initiated tumorigenesis in NOD/SCID Il2rγ-/- mice. Lung TICs express high levels of the oncogenic stem cell factor LIN28B and the metabolic enzyme GLDC. Over-expression of GLDC and other glycine/serine metabolism enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. Metabolomic analysis found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. Clinically, GLDC over-expression, observed in multiple cancer types, predicts poorer survival in lung cancer patients. Our findings establish a novel link between glycine metabolism and tumorigenesis, and provide novel targets for advancing anti-cancer therapy. Total RNA obtained from tumor sphere compared to CD166+ and CD166- selected cells of xenograft, primary tumor and normal donors

ORGANISM(S): Homo sapiens

SUBMITTER: Henry Yang

PROVIDER: E-GEOD-33198 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Glycine decarboxylase is a metabolic oncogene critical for tumor initiating cells and tumorigenesis in lung cancer

Project description:New approaches to cancer therapies could benefit from a better understanding of the molecular determinants critical to tumor initiating cells (TICs). Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). From a broad range of primary NSCLC tumors, we isolated CD166+ lung TICs that consistently initiated tumorigenesis in NOD/SCID Il2rγ-/- mice. Lung TICs express high levels of the oncogenic stem cell factor LIN28B and the metabolic enzyme GLDC. Over-expression of GLDC and other glycine/serine metabolism enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. Metabolomic analysis found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. Clinically, GLDC over-expression, observed in multiple cancer types, predicts poorer survival in lung cancer patients. Our findings establish a novel link between glycine metabolism and tumorigenesis, and provide novel targets for advancing anti-cancer therapy.

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Tumor-initiating cell-specific miR-1246 and miR-1290 converge to promote non-small cell lung cancer progression [Illumina]

Project description:The tumor-initiating cell (TIC) model accounts for the phenotypic and functional heterogeneity among cancer cells found within human cancers. MicroRNAs (miRNAs) are key regulatory molecules frequently aberrantly expressed in tumors, and may play important roles in contributing towards tumor heterogeneity and TIC behavior. More recent efforts have focused on miRNAs for diagnosis and as targets for novel therapies. In this study, we identified the miRNAs, miR-1246 and miR-1290, which are crucial for the function of TICs, thereby driving cancer progression in human non-small cell lung cancer (NSCLC). These miRNAs are restricted to patient-derived tumorspheres and CD166+ primary tumor cells, both enriched for TICs. Loss of either miRNA impacted the tumorigenic potential of TICs and their ability to metastasize. Interestingly, longitudinal analyses of serum miR-1246 and miR-1290 levels correlated circulating levels of either miRNA to the clinical response seen in lung cancer patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibition, chemotherapy and radiotherapy. Functionally, direct inhibition of miR-1246 or miR-1290 with locked nucleic acid (LNA) administered systemically, could arrest the growth of established patient-derived tumors xenografted in immunocompromised mice, thus indicating these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.

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