Tumor-initiating cell-specific miR-1246 and miR-1290 converge to promote non-small cell lung cancer progression
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ABSTRACT:
PROVIDER: PRJNA286042 | ENA |
REPOSITORIES: ENA
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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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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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Project description:The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
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