Transcriptional signatures underlying dynamic phenotypic switching and novel disease biomarkers in a linear cellular model of melanoma progression
| Autor: | Ana Luisa Pedroso Ayub, Camila Ferreira de Souza, Hatylas Azevedo, Vinicius Ferreira da Paixão, Miriam Galvonas Jasiulionis, Debora D. Angelo Papaiz, Diogo de Oliveira Pessoa, Alice S. Morais, Flavia Eichemberger Rius, Jérémie Nsengimana, Eduardo M. Reis, Julia Newton-Bishop, João C. Setubal |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Cellular differentiation Phenotypic switching Cell Plasticity EMT Epithelial-to-Mesenchymal Transition Metastasis Phenotype switch Mice 0302 clinical medicine GEO Gene Expression Omnibus Neoplasm Metastasis Melanoma Original Research EMT DEGs Genes Differentially Expressed lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Prognosis Phenotype Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis AJCC American Joint Committee on Cancer Disease Progression Melanocytes Cellular model MSS Melanoma Specific Survival Epithelial-Mesenchymal Transition PCA Principal Component Analysis Biology lcsh:RC254-282 03 medical and health sciences Downregulation and upregulation Cell Line Tumor GO Gene Ontology medicine Biomarkers Tumor Animals Humans RNA Messenger NSG Next-Generation Sequencing Sequence Analysis RNA Gene Expression Profiling Malignancy medicine.disease Disease Models Animal 030104 developmental biology Tumor progression Cancer research Transcriptome PROGNÓSTICO |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 4, Pp 439-455 (2021) Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1476-5586 1522-8002 |
| Popis: | Despite advances in therapeutics, the progression of melanoma to metastasis still confers a poor outcome to patients. Nevertheless, there is a scarcity of biological models to understand cellular and molecular changes taking place along disease progression. Here, we characterized the transcriptome profiles of a multi-stage murine model of melanoma progression comprising a nontumorigenic melanocyte lineage (melan-a), premalignant melanocytes (4C), nonmetastatic (4C11-) and metastasis-prone (4C11+) melanoma cells. Clustering analyses have grouped the 4 cell lines according to their differentiated (melan-a and 4C11+) or undifferentiated/“mesenchymal-like” (4C and 4C11-) morphologies, suggesting dynamic gene expression patterns associated with the transition between these phenotypes. The cell plasticity observed in the murine melanoma progression model was corroborated by molecular markers described during stepwise human melanoma differentiation, as the differentiated cell lines in our model exhibit upregulation of transitory and melanocytic markers, whereas “mesenchymal-like” cells show increased expression of undifferentiated and neural crest-like markers. Sets of differentially expressed genes (DEGs) were detected at each transition step of tumor progression, and transcriptional signatures related to malignancy, metastasis and epithelial-to-mesenchymal transition were identified. Finally, DEGs were mapped to their human orthologs and evaluated in uni- and multivariate survival analyses using gene expression and clinical data of 703 drug-naïve primary melanoma patients, revealing several independent candidate prognostic markers. Altogether, these results provide novel insights into the molecular mechanisms underlying the phenotypic switch taking place during melanoma progression, reveal potential drug targets and prognostic biomarkers, and corroborate the translational relevance of this unique sequential model of melanoma progression. |
| Databáze: | OpenAIRE |
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