Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers
| Autor: | Franklin W. Huang, Pablo Tamayo, Thomas R. Cech, Josh Lewis Stern, Sarah E. Ferrara, James C. Costello, Kevin Hu, Grace Hibshman, William Kim |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Telomerase Mutant medicine.disease_cause 0302 clinical medicine Neoplasms Tumor Microenvironment 2.1 Biological and endogenous factors Gene Regulatory Networks Aetiology Extracellular Signal-Regulated MAP Kinases Promoter Regions Genetic Cancer Mutation Tumor Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Sequence Analysis Chromatin Immunoprecipitation Epithelial-Mesenchymal Transition Oncology and Carcinogenesis Biology Article Cell Line Promoter Regions Small Molecule Libraries 03 medical and health sciences Genetic Cell Line Tumor Genetics medicine Humans Oncology & Carcinogenesis Molecular Biology Transcription factor Neoplastic Sequence Analysis RNA Gene Expression Profiling SNAI2 030104 developmental biology Gene Expression Regulation Cell culture SNAI1 Cancer research RNA Generic health relevance Developmental Biology |
| Zdroj: | Mol Cancer Res Molecular cancer research : MCR, vol 18, iss 7 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | In a substantial fraction of cancers TERT promoter (TERTp) mutations drive expression of the catalytic subunit of telomerase, contributing to their proliferative immortality. We conducted a pan-cancer analysis of cell lines and find a TERTp mutation expression signature dominated by epithelial-to-mesenchymal transition and MAPK signaling. These data indicate that TERTp mutants are likely to generate distinctive tumor microenvironments and intercellular interactions. Analysis of high-throughput screening tests of 546 small molecules on cell line growth indicated that TERTp mutants displayed heightened sensitivity to specific drugs, including RAS pathway inhibitors, and we found that inhibition of MEK1 and 2, key RAS/MAPK pathway effectors, inhibited TERT mRNA expression. Consistent with an enrichment of mesenchymal states in TERTp mutants, cell lines and some patient tumors displayed low expression of the central adherens junction protein E-cadherin, and we provide evidence that its expression in these cells is regulated by MEK1/2. Several mesenchymal transcription factors displayed elevated expression in TERTp mutants including ZEB1 and 2, TWIST1 and 2, and SNAI1. Of note, the developmental transcription factor SNAI2/SLUG was conspicuously elevated in a significant majority of TERTp-mutant cell lines, and knock-down experiments suggest that it promotes TERT expression. Implications: Cancers harboring TERT promoter mutations are often more lethal, but the basis for this higher mortality remains unknown. Our study identifies that TERTp mutants, as a class, associate with a distinct gene and protein expression signature likely to impact their biological and clinical behavior and provide new directions for investigating treatment approaches for these cancers. |
| Databáze: | OpenAIRE |
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