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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Transcriptional signatures underlying dynamic phenotypic switching and novel disease biomarkers in a linear cellular model of melanoma progression

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Author(s):
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Pessoa, Diogo de Oliveira [1] ; Rius, Flavia Eichemberger [2] ; Angelo Papaiz, Debora D. [2] ; Pedroso Ayub, Ana Luisa [2] ; Morais, Alice Santana [2] ; de Souza, Camila Ferreira [2] ; da Paixao, Vinicius Ferreira [1] ; Setubal, Joao Carlos [1] ; Newton-Bishop, Julia [3] ; Nsengimana, Jeremie [3, 4] ; Azevedo, Hatylas [5] ; Reis, Eduardo Moraes [1] ; Jasiulionis, Miriam Galvonas [2]
Total Authors: 13
Affiliation:
[1] Univ Sao Paulo, Dept Bioquim, Inst Quim, Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Pharmacol Dept, Sao Paulo - Brazil
[3] Univ Leeds, Inst Med Res St Jamess, Leeds, W Yorkshire - England
[4] Newcastle Univ, Populat Hlth Sci Inst, Biostat Res Grp, Newcastle, NSW - Australia
[5] Univ Fed Sao Paulo, Dept Surg, Div Urol, Sao Paulo - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Neoplasia; v. 23, n. 4, p. 439-455, APR 2021.
Web of Science Citations: 0
Abstract

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-naive 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. (AU)

FAPESP's process: 17/25321-5 - The role of lncRNA in melanoma progression
Grantee:Ana Luisa Pedroso Ayub
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 19/05641-0 - The role of lncRNAs and regulatory networks regarding lncRNAs, miRNAs e mRNAs in Melanoma progression
Grantee:Ana Luisa Pedroso Ayub
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 18/20775-0 - Non-coding RNAs involved with melanoma genesis and progression
Grantee:Miriam Galvonas Jasiulionis
Support Opportunities: Regular Research Grants
FAPESP's process: 14/01168-5 - Identification of important targets associated with stem-like state and epithelial mesenchymal transition along melanocyte malignant transformation
Grantee:Alice Santana Morais
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 11/18959-7 - Research in the early stages of melanoma genesis of key regulators of epithelial-mesenchymal transition and stem cell-like phenotype epigenetically controlled
Grantee:Alice Santana Morais
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 14/13663-0 - Integrating gene and microRNA expression, methylome and hidroxymethylome data from different phases of melanoma progression.
Grantee:Miriam Galvonas Jasiulionis
Support Opportunities: Regular Research Grants