| 1. |
- Thijssen, Victor L. J. L., et al.
(author)
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Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth
- 2018
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In: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 246:4, s. 447-458
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Journal article (peer-reviewed)abstract
- Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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| 2. |
- Davies, John R, et al.
(author)
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Inherited variation in the PARP1 gene and survival from melanoma
- 2014
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:7, s. 1625-1633
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Journal article (peer-reviewed)abstract
- We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology
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| 3. |
- Wouters, Jasper, et al.
(author)
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Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
- 2017
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In: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 15:1, s. 1-16
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Journal article (peer-reviewed)abstract
- Background: Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses. Methods: We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. Results: We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. Conclusions: Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.
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| 4. |
- Behboudi, Afrouz, 1967, et al.
(author)
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Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)--associated TORC1-MAML2 gene fusion.
- 2005
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In: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 43:2, s. 202-5
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Journal article (peer-reviewed)abstract
- Recent studies have shown that the t(11;19)(q21;p13) translocation in mucoepidermoid carcinomas and benign Warthin's tumors results in a fusion of the N-terminal CREB-binding domain of the cAMP coactivator TORC1 (a.k.a. MECT1 and WAMTP1) to the Notch coactivator MAML2. Here we show that a third tumor type, clear cell hidradenoma of the skin, also expresses this gene fusion. RT-PCR analysis of a clear cell hidradenoma with a t(11;19)(q21;p13) translocation revealed expression of a TORC1-MAML2 fusion transcript consisting of exon 1 of TORC1 fused to exons 2-5 of MAML2. Because the fusion was only detected in a single case, the frequency of this aberration in clear cell hidradenomas remains unknown. These results demonstrate that the t(11;19) in mucoepidermoid carcinoma, Warthin's tumor, and clear cell hidradenoma targets the same genes and results in identical gene fusions, indicating that at least subgroups of these glandular tumors evolve through activation of the same molecular pathways.
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| 5. |
- Nsengimana, Jérémie, et al.
(author)
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Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort.
- 2015
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:13, s. 11683-11693
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Journal article (peer-reviewed)abstract
- Development and validation of robust molecular biomarkers has so far been limited in melanoma research. In this paper we used a large population-based cohort to replicate two published gene signatures for melanoma classification. We assessed the signatures prognostic value and explored their biological significance by correlating them with factors known to be associated with survival (vitamin D) or etiological routes (nevi, sun sensitivity and telomere length). Genomewide microarray gene expressions were profiled in 300 archived tumors (224 primaries, 76 secondaries). The two gene signatures classified up to 96% of our samples and showed strong correlation with melanoma specific survival (P=3x10-4), Breslow thickness (P=5x10-10), ulceration (P=9.x10-8) and mitotic rate (P=3x10-7), adding prognostic value over AJCC stage (adjusted hazard ratio 1.79, 95%CI 1.13-2.83), as previously reported. Furthermore, molecular subtypes were associated with season-adjusted serum vitamin D at diagnosis (P=0.04) and genetically predicted telomere length (P=0.03). Specifically, molecular high-grade tumors were more frequent in patients with lower vitamin D levels whereas high immune tumors came from patients with predicted shorter telomeres. Our data confirm the utility of molecular biomarkers in melanoma prognostic estimation using tiny archived specimens and shed light on biological mechanisms likely to impact on cancer initiation and progression.
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| 6. |
- Vizoso, Miguel, et al.
(author)
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Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR
- 2015
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 21:7, s. 741-
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Journal article (peer-reviewed)abstract
- Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.
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