Abstract:Metastasis is the leading cause of death in patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonisation are poorly understood. Here, we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this, we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. Next, we characterised the genomes and transcriptomes of mouse melanoma c… Show more
“…By contrast, loss of Lfng which suppresses JAG1-induced NOTCH1 signalling in mammary epithelium, in cooperation with MET/CAVEOLIN gene amplification, promotes basal-like breast cancer [109]. LFNG also functions as a tumor suppressor in melanoma metastasis [110], and in mouse models of pancreatic [111] and prostate cancer [112]. These results reveal fundamental roles of Fringe in regulating Notch signalling.…”
Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine-tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O-fucose, O-GlcNAc and O-glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O-glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O-glycosylation in regulating Notch signalling. O-glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O-glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O-glycans on Notch receptors and their differential effects on Notch signalling.
“…By contrast, loss of Lfng which suppresses JAG1-induced NOTCH1 signalling in mammary epithelium, in cooperation with MET/CAVEOLIN gene amplification, promotes basal-like breast cancer [109]. LFNG also functions as a tumor suppressor in melanoma metastasis [110], and in mouse models of pancreatic [111] and prostate cancer [112]. These results reveal fundamental roles of Fringe in regulating Notch signalling.…”
Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine-tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O-fucose, O-GlcNAc and O-glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O-glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O-glycosylation in regulating Notch signalling. O-glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O-glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O-glycans on Notch receptors and their differential effects on Notch signalling.
“…The results indicated that the chemokine CCL5 and CXCL11 expression was significantly decreased in CDKN2A-deleted melanoma cell lines ( Figure 3A ). B16F0 cells were described as CDKN2A null cell line ( 36 ). The CDKN2A expression was restored in B16F0 cells by transfection with the lentivirus containing proximal promoter-drived p16INK4 (the protein product of CDKN2A) expression.…”
T-cell-mediated immune response is the prerequisite for T-cell-based immunotherapy. However, the limitation of T-cell infiltration in solid tumors restricted the therapeutic effect of T-cell-based immunotherapy. The present study screened the molecular and genetic features of The Cancer Genome Atlas (TCGA)-skin cutaneous melanoma (SKCM) cohort, revealing that T-cell infiltration negatively correlated with genome copy number alteration. The analysis of the TCGA-SKCM cohort indicated that the copy number of CDKN2A was significantly decreased in patients with low T-cell infiltration. The results were validated in the other two melanoma cohorts (DFCI, Science 2015, and TGEN, Genome Res 2017). Besides, the immunohistochemistry analysis of CDKN2A and CD8 expression in 5 melanoma in situ and 15 invasive melanoma patients also showed that CD8 expression was decreased in the patients with low CDKN2A expression and there was a positive correlation between CDKN2A and CD8 expression in these patients. Interestingly, the CDKN2A deletion group and the group with low expression of T-cell markers shared similar gene and pathway alteration as compared with the normal CDKN2A group and the group with high expression of T-cell markers, especially the chemokine pathway. Further mechanistic study indicated that CDKN2A enhanced T cell recruitment and chemokine expression possibly through modulating MAPK and NF-κB signaling pathways in a cell cycle–dependent manner. Finally, we also found that CDKN2A deletion negatively correlated with the expression of T-cell markers in many other cancer types. In conclusion, CDKN2A deletion could inhibit T cell infiltration by inhibiting chemokine expression in a cell cycle dependent manner.
“…Other genes are related to apoptosis ( Casp7 ) and mitotic arrest ( Fbl2 ) [ 43 ]. In addition, Lfng (Lunatic fringe) encodes a glycosyltransferase that inhibits metastasis in melanoma cells [ 44 ]. Fig.…”
Background: We have previously developed a murine cellular system that models the transformation from melanocytes to metastatic melanoma cells. This model was established by cycles of anchorage impediment of melanocytes and consists of four cell lines: differentiated melanocytes (melan-a), pre-malignant melanocytes (4C), malignant (4C11−), and metastasis-prone (4C11+) melanoma cells. Here, we searched for transcriptional and epigenetic signatures associated with melanoma progression and metastasis by performing a gene co-expression analysis of transcriptome data and a mass-spectrometry-based profiling of histone modifications in this model. Results: Eighteen modules of co-expressed genes were identified, and some of them were associated with melanoma progression, epithelial-to-mesenchymal transition (EMT), and metastasis. The genes in these modules participate in biological processes like focal adhesion, cell migration, extracellular matrix organization, endocytosis, cell cycle, DNA repair, protein ubiquitination, and autophagy. Modules and hub signatures related to EMT and metastasis (turquoise, green yellow, and yellow) were significantly enriched in genes associated to patient survival in two independent melanoma cohorts (TCGA and Leeds), suggesting they could be sources of novel prognostic biomarkers. Clusters of histone modifications were also linked to melanoma progression, EMT, and metastasis. Reduced levels of H4K5ac and H4K8ac marks were seen in the pre-malignant and tumorigenic cell lines, whereas the methylation patterns of H3K4, H3K56, and H4K20 were related to EMT. Moreover, the metastatic 4C11+ cell line showed higher H3K9me2 and H3K36me3 methylation, lower H3K18me1, H3K23me1, H3K79me2, and H3K36me2 marks and, in agreement, downregulation of the H3K36me2 methyltransferase Nsd1.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
