| Texto completo | |
| Autor(es): |
Monteiro de Assis, Leonardo Vinicius
;
Kinker, Gabriela Sarti
;
Moraes, Maria Nathalia
;
Markus, Regina P.
;
Fernandes, Pedro Augusto
;
de lauro Castrucci, Ana Maria
Número total de Autores: 6
|
| Tipo de documento: | Artigo Científico |
| Fonte: | FRONTIERS IN ONCOLOGY; v. 8, p. 11-pg., 2018-06-12. |
| Resumo | |
Introduction: Melanoma is the most lethal type of skin cancer, with increasing incidence and mortality rates worldwide. Multiple studies have demonstrated a link between cancer development/progression and circadian disruption; however, the complex role of tumor-autonomous molecular clocks remains poorly understood. With that in mind, we investigated the pathophysiological relevance of clock genes expression in metastatic melanoma. Methods: We analyzed gene expression, somatic mutation, and clinical data from 340 metastatic melanomas from The Cancer Genome Atlas, as well as gene expression data from 234 normal skin samples from genotype-tissue expression. Findings were confirmed in independent datasets. Results: In melanomas, the expression of most clock genes was remarkably reduced and displayed a disrupted pattern of co-expression compared to the normal skins, indicating a dysfunctional circadian clock. Importantly, we demonstrate that the expression of the clock gene aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) positively correlates with patient overall survival and with the expression of T-cell activity and exhaustion markers in the tumor bulk. Accordingly, high BMAL1 expression in pretreatment samples was significantly associated with clinical benefit from immune checkpoint inhibitors. The robust intratumoral T-cell infiltration/activation observed in patients with high BMAL1 expression was associated with a decreased expression of key DNA-repair enzymes, and with an increased mutational/neoantigen load. Conclusion: Overall, our data corroborate previous reports regarding the impact of BMAL1 expression on the cellular DNA-repair capacity and indicate that alterations in the tumor-autonomous molecular clock could influence the cellular composition of the surrounding microenvironment. Moreover, we revealed the potential of BMAL1 as a clinically relevant prognostic factor and biomarker for T-cell-based immunotherapies. (AU) | |
| Processo FAPESP: | 12/50214-4 - Mecanismos de ajuste do relógio por luz e temperatura: aspectos filogenéticos |
| Beneficiário: | Ana Maria de Lauro Castrucci |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 14/16412-9 - Mecanismos de termo-modulação de genes de relógio em tecidos periféricos de mamíferos: papel dos canais TRP |
| Beneficiário: | Maria Nathália de Carvalho Magalhães Moraes Figueira Borges |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 14/27287-0 - Caracterização do sistema melatonérgico de gliomas humanos e sua implicação sobre o grau de agressividade e invasibilidade tumoral |
| Beneficiário: | Gabriela Sarti Kinker |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado Direto |
| Processo FAPESP: | 13/24337-4 - Mecanismos de modulação de genes de relógio em melanócitos normais (melan-A) e transformados (melanoma B16-F10) por UVA e luz azul |
| Beneficiário: | Leonardo Vinícius Monteiro de Assis |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado Direto |