Exploring the role of NRF2 and circadian cycle as mediators of tumor resistance to...
| Full text | |
| Author(s): |
Monteiro de Assis, Leonardo Vinicius
[1]
;
Kinker, Gabriela Sarti
[2]
;
Moraes, Maria Nathalia
[1]
;
Markus, Regina P.
[2]
;
Fernandes, Pedro Augusto
[2]
;
de lauro Castrucci, Ana Maria
[3, 1]
Total Authors: 6
|
| Affiliation: | [1] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Comparat Physiol Pigmentat, Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Neuroimmunemodulat, Sao Paulo - Brazil
[3] Univ Virginia, Dept Biol, Charlottesville, VA - USA
Total Affiliations: 3
|
| Document type: | Journal article |
| Source: | FRONTIERS IN ONCOLOGY; v. 8, JUN 12 2018. |
| Web of Science Citations: | 6 |
| Abstract | |
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) | |
| FAPESP's process: | 14/27287-0 - Characterization of the melatonergic system of human gliomas and its implication on tumor aggressiveness and invasiveness |
| Grantee: | Gabriela Sarti Kinker |
| Support type: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 13/24337-4 - Clock genes modulation by UVA/blue light stimulation in normal melan-A and transformed B-16 melanocytes |
| Grantee: | Leonardo Vinícius Monteiro de Assis |
| Support type: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 14/16412-9 - Mechanisms of clock genes thermo-modulation in peripheral tissue of mammals: role of TRP channels |
| Grantee: | Maria Nathália de Carvalho Magalhães Moraes Figueira Borges |
| Support type: | Scholarships in Brazil - Post-Doctorate |
| FAPESP's process: | 12/50214-4 - Biological clock setting by light and temperature: phylogenetic aspects |
| Grantee: | Ana Maria de Lauro Castrucci |
| Support type: | Research Projects - Thematic Grants |