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Nonmelanoma skin cancers (NMSCs), are among the most common human malignancies.,Current methods for their prevention include avoidance of natural and artificial sources of UV radiation, photoprotective clothing and sunscreens.,However, these methods have proven to be inadequate in stemming the rise in skin cancer incid... | Induction of DNA damage by UVB and UVA radiation may generate mutations and genomic instability leading to carcinogenesis.,Therefore, skin cells being repeatedly exposed to ultraviolet (UV) light have acquired multilayered protective mechanisms to avoid malignant transformation.,Besides extensive DNA repair mechanisms,... | 1 |
Circular RNAs (circRNAs) have been reported to have critical regulatory roles in tumor biology.,However, their contribution to melanoma remains largely unknown.,CircRNAs derived from oncogene CD151 were detected and verified by analyzing a large number of melanoma samples through quantitative real-time polymerase chain... | Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy.,Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules.,LncRNAs have been implicated in cancer development and response to different therapeutics and are thu... | 1 |
The metastatic Skin Cutaneous Melanoma (SKCM) has been associated with diminished survival rates and high mortality rates worldwide.,Thus, segregating metastatic melanoma from the primary tumors is crucial to employ an optimal therapeutic strategy for the prolonged survival of patients.,The SKCM mRNA, miRNA and methyla... | Despite the extensive research approaches applied to characterise malignant melanoma, no specific molecular markers are available that are clearly related to the progression of this disease.,In this study, our aims were to define a gene expression signature associated with the clinical outcome of melanoma patients and ... | 1 |
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients.,Since most patients do not respond, predictive biomarkers to guide treatment selection are needed.,We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response... | Cells release multiple, distinct, forms of extracellular vesicles including structures known as microvesicles which are known to alter the extracellular environment.,Despite growing understanding of microvesicle biogenesis, function, and contents, mechanisms regulating cargo delivery and enrichment remain largely unkno... | 1 |
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM).,We report the results of an international two-stage meta-analysis of 11 genome-wide association studies (GWAS, five unpublished) of CMM and Stage two datasets, totaling 15,990 cases and 26,409 controls.,Five l... | Common acquired melanocytic nevi are benign neoplasms that are composed of small uniform melanocytes and typically present as flat or slightly elevated, pigmented lesions on the skin.,We describe two families with a new autosomal dominant syndrome characterized by multiple skin-colored, elevated melanocytic tumors.,In ... | 1 |
Activated RAS promotes dimerization of members of the RAF kinase family1-3.,ATP-competitive RAF inhibitors activate ERK signaling4-7 by transactivating RAF dimers4.,In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity.,This tumor-... | Activating mutations in BRAF kinase are common in melanomas.,Clinical trials with PLX4032, the mutant-BRAF inhibitor, show promising preliminary results in patients selected for the presence of V600E mutation.,However, activating V600K mutation is the other most common mutation, yet patients with this variant are curre... | 1 |
Approximately one‐third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease.,Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site.,Such data could inform ima... | Merkel cell polyomavirus (MCV) causes the majority of human Merkel cell carcinomas (MCC) and encodes a small T (sT) antigen that transforms immortalized rodent fibroblasts in vitro.,To develop a mouse model for MCV sT-induced carcinogenesis, we generated transgenic mice with a flox-stop-flox MCV sT sequence homologousl... | 1 |
Squamous cell carcinomas (SCC), including cutaneous SCCs, are by far the most frequent cancers in humans, accounting for 80% of all newly diagnosed malignancies worldwide.,The old dogma that SCC develops exclusively from stem cells (SC) has now changed to include progenitors, transit-amplifying and differentiated short... | Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level.,However, the posttranscriptional regulation of BAX is under explored.,In this study, we identified BAX as the novel downstream target of miR-365, which ... | 1 |
Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy.,These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells.,Tumor-resident myeloid cells and selected lymphocyte populations reta... | Melanoma is among the most aggressive tumors, and the occurrence of metastasis leads to a precipitous drop in the patients' survival.,Therefore, identification of metastasis-associated biomarkers and therapeutic targets will contribute a lot to improving melanoma theranostics.,Recently, microRNAs (miRNAs) have been imp... | 1 |
In response to the dynamic intra‐tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia‐associated transcription factor (MITF).,The response to hypoxia is driven by hypoxia‐inducible transcription factors (HIFs) that reprogram metabolism and... | Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading.,Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing tra... | 1 |
While multiple mechanisms of BRAFV600-mutant melanoma resistance to targeted MAPK signaling inhibitors (MAPKi) have been reported, the epigenetic regulation of this process remains undetermined.,Here, using a CRISPR-Cas9 screen targeting chromatin regulators, we discover that haploinsufficiency of the histone deacetyla... | Cancer is a disease consisting of both genetic and epigenetic changes.,While increasing evidence demonstrates that tumour progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and progression currently remains unclear.,Here, we report that the histone ... | 1 |
Cell-to-cell variability generates subpopulations of drug-tolerant cells that diminish the efficacy of cancer drugs.,Efficacious combination therapies are thus needed to block drug-tolerant cells via minimizing the impact of heterogeneity.,Probabilistic models such as Bliss independence have been developed to evaluate ... | Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading.,Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing tra... | 1 |
Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells.,We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM)... | Melanoma cells rely on developmental programs during tumor initiation and progression.,Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a−/− melanoma model and that its expression is necessary for primary melanoma formation.,Surprisingly, while Sall4 loss prevents ... | 1 |
In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma.,The early steps of this transformation have taken place in research laborator... | Tumor spreading is associated with the degradation of extracellular matrix proteins, mediated by the overexpression of matrix metalloproteinase 9 (MMP-9).,Although, such overexpression was linked to epigenetic promoter methylation, the role of intragenic methylation was not clarified yet.,Melanoma was used as tumor mod... | 1 |
The failure in achieving a durable clinical immune response against cancer cells depends on the ability of cancer cells to establish a microenvironment that prevent cytotoxic immune cells to infiltrate tumors and kill cancer cells.,Therefore, the key approach to achieving successful antitumor immune response is to harn... | T cell trafficking at vascular sites has emerged as a key step in antitumor immunity.,Chemokines are credited with guiding the multistep recruitment of CD8+ T cells across tumor vessels.,However, the multiplicity of chemokines within tumors has obscured the contributions of individual chemokine receptor/chemokine pairs... | 1 |
In the present study, the phenotype of melanoma cells resistant to dabrafenib (a B-RAF inhibitor) was investigated, to shed more light on melanoma resistance to B-RAF inhibition.,Melanoma cells resistant to dabrafenib were generated using 3 different cell lines, A375, 397 and 624.38, all carrying B-RAFV600E, and they w... | Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion.,Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma.,Changing ex... | 1 |
The diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment.,We have previously demonstrated that the morphological and functional phenotypes of melanoma can be dynamically altered u... | Nuclear factor-κB (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB.,NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been unclear.,Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), pr... | 1 |
Long non-coding RNAs (lncRNAs) are involved in tumorigenesis.,Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNAs, is associated with the growth and metastasis of many human tumors, but its biological roles in malignant melanoma remain unclear.,In this study, the aberrant up-regulation of MALAT1... | Long non-coding RNAs (lncRNAs) have been shown to be implicated in the complex network of cancer including malignant melanoma and play important roles in tumorigenesis and progression.,However, their functions and downstream mechanisms are largely unknown.,This study aimed to investigate whether BRAF-activated non-codi... | 1 |
Melanoma is characterised by its ability to metastasise at early stages of tumour development.,Current clinico‐pathologic staging based on the American Joint Committee on Cancer criteria is used to guide surveillance and management in early‐stage disease, but its ability to predict clinical outcome has limitations.,Her... | KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease.,Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequenc... | 1 |
Genes in the S100 family are abnormally expressed in a variety of tumor cells and are associated with clinical pathology, but their prognostic value in melanoma patients has not yet been fully elucidated.,In this study, we extracted and profiled S100 family mRNA expression data and corresponding clinical data from the ... | BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma.,We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.,Allele-specific quantitative... | 1 |
Hotspot mutations in the spliceosome gene SF3B1 are reported in ∼20% of uveal melanomas.,SF3B1 is involved in 3′-splice site (3′ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear.,Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1R625/K666 mu... | BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families.,These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alle... | 1 |
The prognosis of metastatic melanoma is very poor, due to the development of drug resistance.,Cancer stem cells (CSCs) may play a crucial role in this mechanism, contributing to disease relapse.,We first characterized CSCs in melanoma cell lines.,We observed that A375 (but not BLM) cells are able to form melanospheres ... | Melanoma is the most dangerous and treatment-resistant skin cancer.,Tumor resistance and recurrence are due to the persistence in the patient of aggressive cells with stem cell features, the cancer stem cells (CSC).,Recent evidences have shown that CSC display a distinct metabolic profile as compared to tumor bulk popu... | 1 |
BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma.,We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.,Allele-specific quantitative... | Growing evidence is showing that metastatic cell populations are able to transfer their characteristics to less malignant cells.,Exosomes (EXOs) are membrane vesicles of endocytic origin able to convey their cargo of mRNAs, microRNAs (miRs), proteins and lipids from donors to proximal as well as distant acceptor cells.... | 1 |
Melanoma, the most dangerous type of cutaneous neoplasia, contributes to about 75% of all skin cancer-related deaths.,Thus, searching for new melanoma treatment options is an important field of study.,The current study was designed to assess whether the condition of mild and low-dose UVA radiation augments the lomeflox... | The prognosis of metastatic melanoma is very poor, due to the development of drug resistance.,Cancer stem cells (CSCs) may play a crucial role in this mechanism, contributing to disease relapse.,We first characterized CSCs in melanoma cell lines.,We observed that A375 (but not BLM) cells are able to form melanospheres ... | 1 |
Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye.,Here, we performed multi-region DNA sequencing of primary uveal melanomas and their matched metastases from 35 patients.,We observed novel driver mutations and established the order in which thes... | Uveal melanoma (UM) is the most common cancer of the eye in adults.,Many UM patients develop metastases for which no curative treatment has been identified.,Novel therapeutic approaches are therefore urgently needed.,UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to... | 1 |
In the present study, we analyzed the role of microRNA-194 circulating regulated human melanoma cell growth.,We found that microRNA-194 expression was markedly suppressed in human melanoma patients, compared with negative control group.,Next, disease-free survival (DFS) and overall survival (OS) of high expression in h... | Long non-coding RNAs (lncRNAs) have been shown to be implicated in the complex network of cancer including malignant melanoma and play important roles in tumorigenesis and progression.,However, their functions and downstream mechanisms are largely unknown.,This study aimed to investigate whether BRAF-activated non-codi... | 1 |
MITF (microphthalmia-associated transcription factor) represents a melanocytic lineage-specific transcription factor whose role is profoundly extended in malignant melanoma.,Over the last few years, the function of MITF has been tightly connected to plasticity of melanoma cells.,MITF participates in executing diverse m... | Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5.,Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma ... | 1 |
Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas.,Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver.,Despite its clinical and genetic heterog... | Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages.,The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.,Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor we... | 1 |
Whereas significant anti-tumor responses are observed in most BRAFV600E-mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops.,Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) ... | Rationale: Malignant melanoma (MM) is the cutaneous neoplasia with the greatest mortality rates and one of the malignancies with the highest potential of dissemination.,The prognosis of patients with metastatic MM is grim, with a 5-years survival rate between 5-19%, and is dictated by the location and the number of met... | 1 |
Melanomas are tumors originating from melanocytes and tend to show early metastasis secondary to the loss of cellular adhesion in the primary tumor, resulting in high mortality rates.,Cancer-specific active immunotherapy is an experimental form of treatment that stimulates the immune system to recognize antigens on the... | Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected.,Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exac... | 1 |
Long non-coding RNAs (lncRNAs) are a largely uncharacterized group of non-coding RNAs with diverse regulatory roles in various biological processes.,Recent observations have elucidated the functional roles of lncRNAs in cutaneous biology, e.g. in proliferation and differentiation of epidermal keratinocytes and in cutan... | Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), together known as keratinocyte cancers (KCs), are the commonest cancer in white ethnic populations.,Recent improvements to registry data collection in England has allowed more accurate analysis of the epidemiology of BCC and cSCC and for the first... | 1 |
The study aims to evaluate the effects of miR-136 on the proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) of melanoma cells by targetting premelanosome protein (PMEL) through the Wnt signaling pathway.,After establishment of melanoma mouse models, melanoma (model group) and normal tissues (normal g... | Growing evidence is showing that metastatic cell populations are able to transfer their characteristics to less malignant cells.,Exosomes (EXOs) are membrane vesicles of endocytic origin able to convey their cargo of mRNAs, microRNAs (miRs), proteins and lipids from donors to proximal as well as distant acceptor cells.... | 1 |
Histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms.,As a result, more sophisticated and objective methods have been sought.,The goal of this study was to identify a gene expression signature that reliably differentiated benign and malignant melan... | Several lines of evidence suggest a dichotomy between immune active and quiescent cancers, with the former associated with a good prognostic phenotype and better responsiveness to immunotherapy.,Central to such dichotomy is the master regulator of the acute inflammatory process interferon regulatory factor (IRF)-1.,How... | 1 |
Response to targeted therapies varies significantly despite shared oncogenic mutations.,Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace.,Resistance to BRAF inhibitors have been attributed to the activation of various receptor... | Cathepsins represent a group of proteases involved in determining the metastatic potential of cancer cells.,Among these are cysteinyl- (e.g. cathepsin B and cathepsin L) and aspartyl-proteases (e.g. cathepsin D), normally present inside the lysosomes as inactive proenzymes.,Once released in the extracellular space, cat... | 1 |
Melanoma affects about 6000 patients a year in Spain.,A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients.,The diagnosis must be histological and determination of BR... | Epidemiological studies propose that obesity increases the risk of several cancers, including melanoma.,Obesity increases the expression of leptin, a multifunctional peptide produced predominantly by adipocytes which may promote tumor growth.,Several recently experiments have suggested that the tumors growth is in need... | 1 |
Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone.,These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targete... | Mutations in GNAQ and GNA11, encoding the oncogenic G-protein alpha subunit q and 11, respectively, occur frequently in the majority of uveal melanomas.,Exons 4 and 5 from GNAQ and GNA11 were amplified and sequenced from 92 ciliary body and choroidal melanomas.,The mutation status was correlated with disease-free survi... | 1 |
A major challenge for managing melanoma is its tumour heterogeneity based on individual co‐existing melanoma cell phenotypes.,These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative.,Melanoma phenotype... | Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes.,Guidelines for melanoma genetic testing have been published as an informal “rule of twos and threes,” but these guidelines apply to CDKN2A testing and are not intended for the more recently describ... | 1 |
Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation.,NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signa... | A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines.,The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin... | 1 |
Vascular pericytes are an important cellular component in the tumor microenvironment, however, their role in supporting cancer invasion is poorly understood.,We hypothesized that PDGF-BB could be involved in the transition of human retinal pericytes (HRPC) in cancer-activated fibroblasts (CAF), induced by the 92.1 uvea... | Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye.,Here, we performed multi-region DNA sequencing of primary uveal melanomas and their matched metastases from 35 patients.,We observed novel driver mutations and established the order in which thes... | 1 |
Melanoma cells display distinct intrinsic phenotypic states.,Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annot... | Melanoma is the deadliest form of skin cancer, affecting men more frequently and severely than women.,Although recent studies suggest that differences in activity of the androgen receptor (AR) underlie the observed sex bias, little is known about AR activity in melanoma.,Here we show that AR and EGR1 bind to the long n... | 1 |
Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1.,To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of... | Uveal melanoma is a highly aggressive cancer with a strong propensity for metastasis, yet little is known about the biological mechanisms underlying this metastatic potential.,We recently showed that most metastasizing uveal melanomas, which exhibit a class 2 gene expression profile, contain inactivating mutations in t... | 1 |
Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer.,Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK).,However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet.... | Dendritic cell (DC) based vaccines have emerged as a promising immunotherapy for cancers.,However, most DC vaccines so far have achieved only limited success in cancer treatment.,Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune... | 1 |
Supplemental Digital Content is available in the text.,Management of PD-1 blockade resistance in metastatic melanoma (MM) remains challenging.,Immunotherapy or chemotherapy alone provides limited benefit in this setting.,Chemo-immunotherapy (CIT) has demonstrated favorable efficacy and safety profiles in lung cancer.,O... | Every biological experiment requires a choice of throughput balanced against physiological relevance.,Most primary drug screens neglect critical parameters such as microenvironmental conditions, cell-cell heterogeneity, and specific readouts of cell fate for the sake of throughput.,Here we describe a methodology to qua... | 1 |
Rationale: Melanoma is an aggressive tumor of the skin and drug resistance is still a major problem in melanoma therapy.,Novel targets and effective agents to overcome drug resistant melanoma are urgently needed in clinical therapy.,Methods: Gene Expression Omnibus (GEO) database analysis, pathway enrichment analysis, ... | The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown.,BRAF/MEK inhibition (BRAF/MEKi), single agent anti‐PD‐1 (aPD‐1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively comp... | 1 |
The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis.,Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly... | Long non-coding RNAs (lncRNAs) are involved in tumorigenesis.,Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNAs, is associated with the growth and metastasis of many human tumors, but its biological roles in malignant melanoma remain unclear.,In this study, the aberrant up-regulation of MALAT1... | 1 |
BRAF mutations are frequent in cutaneous melanomas and BRAF inhibitors(BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients.,However, acquired drug resistance can occur rapidly and tumor(s) often progress thereafter.,Various mechanisms of BRAFi resistance have recently been described; however... | Activated RAS promotes dimerization of members of the RAF kinase family1-3.,ATP-competitive RAF inhibitors activate ERK signaling4-7 by transactivating RAF dimers4.,In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity.,This tumor-... | 1 |
Melanoma is a highly lethal cutaneous cancer with the tendency for early invasion and metastasis.,Integrated miRNA transcriptome sequence analysis of human melanoma tumors and adjacent control tissues identified 17 miRNAs differentially expressed in melanoma tissues: let-7a-5p, let-7b-5p, let-7c, miR-374a-3p, miR-100-5... | Dynamic N6-methyladenosine (m6A) RNA modification generated and erased by N6-methyltransferases and demethylases regulates gene expression, alternative splicing and cell fate.,Ocular melanoma, comprising uveal melanoma (UM) and conjunctival melanoma (CM), is the most common primary eye tumor in adults and the 2nd most ... | 1 |
To explore the effect of VEGF (vascular endothelial growth factor) on the vasculogenic mimicry (VM) formation of Choroidal Melanoma (CM) through PI3k signal pathway, to find novel targets for CM therapy.,This research investigated the molecular mechanism of VEGF promoting VM formation of CM.,First, we evaluated the exp... | Melanoma cells can switch their phenotypes in response to microenvironmental insults.,Heterogeneous melanoma populations characterized by long-term growth and a high self-renewal capacity can be obtained in vitro in EGF(+)bFGF(+) medium whilst invasive potential of melanoma cells is increased in serum-containing cultur... | 1 |
The effect of apatinib on the formation of vasculogenic mimicry (VM) was studied in a malignant melanoma cell line.,MUM-2B cells cultured in three-dimensional Matrigel were treated with varying concentrations (0, 0.01, 0.05, 0.1, 0.5 μmol/L) of apatinib to test its effect on VM in vitro, followed by MTT proliferation a... | Glycolytic reprogramming is a typical feature of many cancers; however, key regulators of glucose metabolism reengineering are poorly understood, especially in cutaneous squamous cell carcinoma (cSCC).,Here, Homeobox A9 (HOXA9), a direct target of onco-miR-365, is identified to be significantly downregulated in cSCC tu... | 1 |
Deregulation of miRNAs contributes to the development of distinct cancer types, including melanoma, an aggressive form of skin cancer characterized by high metastatic potential and poor prognosis.,The expression of a set of 580 miRNAs was investigated in a model of murine melanoma progression, comprising non-metastatic... | Skin cancer, including melanoma, basal cell carcinoma and cutaneous squamous cell carcinoma, has one of the highest global incidences of any form of cancer.,In 2016 more than 16,000 people were diagnosed with melanoma in the UK.,Over the last decade the incidence of melanoma has increased by 50% in the UK, and about on... | 1 |
Drug resistance remains a vexing problem in the treatment of cancer patients.,While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy.,Here we developed a co-culture system to systematically assay the abili... | Melanoma cells driven by mutant B-RAF are highly resistant to chemotherapeutic treatments.,Recent Phase 1 results with PLX4032/RG7204/Vemurafenib, which selectively inhibits B-RAF/MEK/ERK1/2 signaling in mutant B-RAF cells, has given encouragement to this struggling field.,Nearly all patients in the phase 1-3 studies s... | 1 |
Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance.,Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availabili... | Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma.,To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma.,Our data demonstrate that high serum LDH ... | 1 |
BCL2 19 kD protein-interacting protein 3 (BNIP3) is a BH3-containing protein of the BCL-2 family; it can regulate cell death, autophagy, and cytoprotection.,The upregulation of BNIP3 has been reported to relate to progression and poor prognosis in different cancer types.,However, the clinical significance of BNIP3 in u... | Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease.,Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis.,There is currently little published evidence ... | 1 |
Due to the critical impact of active AP-1 transcription factors in melanoma, it is important to define their target genes and to identify and ultimately inhibit oncogenic signals.,Here we mapped the genome-wide occupancy of the AP-1 family member c-Jun in different melanoma cells and correlated AP-1 binding with transc... | Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer.,The latter is due to its viral or UV-associated carcinogenesis.,For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression.,Indeed, a reduced HLA class-I expression was observed ... | 1 |
The co-receptor lymphocyte-activation gene-3 (LAG3, LAG-3, CD223) is a potential target for immune checkpoint inhibition immunotherapies.,However, little is known about the biological and clinical significance of LAG3 DNA methylation in melanoma and its microenvironment.,We evaluated LAG3 promoter and gene body methyla... | UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter.,In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenc... | 1 |
The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors.,We therefore interrogated a historical cohort of patients free of the confo... | The clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance.,In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro.,Anti-tumor effects... | 1 |
Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma.,Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration.,We show that PRL3 binds to the RNA helicase DDX21, thereby restricting pro... | The most common mutation in melanoma, BRAF(V600E), activates the BRAF serine/threonine kinase and causes excessive MAPK pathway activity1,2.,BRAF(V600E)mutations are also present in benign melanocytic nevi3, highlighting the importance of additional genetic alterations in the genesis of malignant tumors.,Such changes i... | 1 |
Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome.,Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-bi... | Ipilimumab improves the survival of metastatic melanoma patients.,Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment.,The aim of this study was to identify an upfront marker for treatment benefit.,A total of 187 metastatic melanoma patients treated in three... | 1 |
Uveal melanoma is the most common primary intraocular malignancy in adults.,Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases.,The median survival for patients with liver metastases is be... | TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2.,The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations.,Flow cytometry, Western blots and metabolic tracer uptake assays were use... | 1 |
Uveal melanoma is a highly aggressive cancer with a strong propensity for metastasis, yet little is known about the biological mechanisms underlying this metastatic potential.,We recently showed that most metastasizing uveal melanomas, which exhibit a class 2 gene expression profile, contain inactivating mutations in t... | Melanoma is notable for its metastatic propensity, lethality in the advanced setting, and association with ultraviolet (UV) exposure early in life1.,To obtain a comprehensive genomic view of melanoma, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA.,A wide range of point mutation rates was ... | 1 |
In vitro studies and mathematical models are now being widely used to study the underlying mechanisms driving the expansion of cell colonies.,This can improve our understanding of cancer formation and progression.,Although much progress has been made in terms of developing and analysing mathematical models, far less pr... | Melanocytic nevi are benign proliferations that sometimes turn into malignant melanoma in a way that is still unclear from the biochemical and genetic point of view.,Diagnostic and prognostic tools are then mostly based on dermoscopic examination and morphological analysis of histological tissues.,To investigate the ro... | 1 |
The overall 5-year survival for melanoma is 91%.,However, if distant metastasis occurs (stage IV), cure rates are < 15%.,Hence, melanoma detection in earlier stages (stages I-III) maximises the chances of patient survival.,We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (s... | Long non-coding RNAs (lncRNAs) have been shown to be implicated in the complex network of cancer including malignant melanoma and play important roles in tumorigenesis and progression.,However, their functions and downstream mechanisms are largely unknown.,This study aimed to investigate whether BRAF-activated non-codi... | 1 |
Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year.,Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment ... | The incidence of melanoma is increasing worldwide, and the prognosis for patients with high-risk or advanced metastatic melanoma remains poor despite advances in the field.,A systematic literature review of treatments for advanced, metastatic disease was conducted to present the success of current treatments and the pr... | 1 |
In Australia, more money is spent on skin cancer than any other malignancy.,Despite this, the mortality rate of melanoma, the deadliest form, has steadily increased over the past 50 years.,Diagnostic imprecision and a lack of complimentary molecular biomarkers are partially responsible for this lack of progress.,Whole-... | Over two-thirds of melanomas have activating mutations in B-Raf, leading to constitutive activation of the B-Raf/MKK/ERK signaling pathway.,The most prevalent mutation, B-RafV600E, promotes cancer cell behavior through mechanisms that are still incompletely defined.,Here, we used a sensitive microarray profiling platfo... | 1 |
Targeted inhibitors elicit heterogeneous clinical responses in genetically stratified groups of patients.,While most studies focus on tumor intrinsic properties, factors in the tumor microenvironment were recently found to modulate the response to inhibitors.,Here, we show that in cutaneous BRAF V600E melanoma, the cyt... | Melanoma is the most highly malignant skin cancer, and nucleotide excision repair (NER) is involved in melanoma susceptibility.,In this analysis of 1042 melanoma patients, we evaluated whether genetic variants of NER genes may predict survival outcome of melanoma patients.,We used genotyping data of 74 tagging single n... | 1 |
Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation.,Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma.,Therefore, molecu... | T-cell-based immunotherapies are promising treatments for cancer patients.,Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies.,From a screen of 850 bioactive compounds, we identify HSP90 inhibito... | 1 |
Melanoma is one of the most immunologic malignancies based on its higher prevalence in immune-compromised patients, the evidence of brisk lymphocytic infiltrates in both primary tumors and metastases, the documented recognition of melanoma antigens by tumor-infiltrating T lymphocytes and, most important, evidence that ... | Melanoma is an aggressive malignancy of melanocytes and most commonly arises in the skin.,In 2002, BRAF gene mutations were identified in melanoma, and this finding resulted in the development of several small-molecule molecular inhibitors that specifically targeted the BRAF V600E mutation.,The development of targeted ... | 1 |
Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis.,As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of ... | Cutaneous melanoma is an aggressive cancer with a poor prognosis for patients with advanced disease.,The identification of several key molecular pathways implicated in the pathogenesis of melanoma has led to the development of novel therapies for this devastating disease.,In melanoma, both the Ras/Raf/MEK/ERK (MAPK) an... | 1 |
The cellular defense system known as global-genome nucleotide excision repair (GG-NER) safeguards genome stability by eliminating a plethora of structurally unrelated DNA adducts inflicted by chemical carcinogens, ultraviolet (UV) radiation or endogenous metabolic by-products.,Xeroderma pigmentosum group C (XPC) protei... | The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins.,The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotyp... | 1 |
Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood1-4; however, the reason for this is unclear.,Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood.,Immunocompr... | Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers.,Primary disease is efficiently controlled by surgery or radiation therapy, but about ... | 1 |
Interleukin-9 is a T cell cytokine that acts through a γC-family receptor on target cells.,We determined that T cells from mice deficient in the TH17 pathway genes ROR-γ and IL-23R produced abundant IL-9, and observed significant growth inhibition of B16F10 melanoma tumor in these mice.,IL-9 blocking antibodies reverse... | Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways.,MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V6... | 1 |
Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity.,Taking this into account, we analyzed, using multiparametric flow cytometry, the co-expression of the melanoma markers melanoma cell adhesion molecule and melanoma-associ... | Current therapeutic regimens attempt to eliminate all malignant cells of a melanoma lesion.,Pre-clinical data, however, indicate that melanoma is maintained by a minor subset of cancer cells, which are characterized by CD20 expression.,We attempted to eliminate those cells in a progressing, chemotherapy-refractory meta... | 1 |
CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma.,Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype.,All known families with CDK4 germline mutations (n=17) were re... | Whole-genome sequencing identifies a novel germline variant in the oncogene MITF, which is associated with the development of melanoma.,The online version of this article (doi:10.1038/nature10630) contains supplementary material, which is available to authorized users.,Two papers in this issue of Nature demonstrate tha... | 1 |
The therapeutic landscape in metastatic melanoma has changed dramatically in the last decade, with the success of immune checkpoint inhibitors resulting in durable responses for a large number of patients.,For patients with BRAF mutations, combinations of BRAF and MEK inhibitors demonstrated response rates and benefit ... | microRNAs constitute a complex class of pleiotropic post-transcriptional regulators of gene expression involved in the control of several physiologic and pathologic processes.,Their mechanism of action is primarily based on the imperfect matching of a seed region located at the 5′ end of a 21-23 nt sequence with a part... | 1 |
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma‐prone families.,In our study we comprehensively characterized 488 melanoma cases from 451 non‐CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes usi... | Both the combination of nivolumab + ipilimumab and single‐agent anti‐PD‐1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma.,As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti‐PD‐1 immunotherapy are needed to un... | 1 |
Uveal melanoma (UM) development and progression is correlated with specific molecular changes.,Recurrent mutations in GNAQ and GNA11 initiate UM development while tumour progression is correlated with monosomy of chromosome 3 and gain of chromosome 8q.,Hence, molecular analysis of UM is useful for diagnosis and prognos... | Elevated levels of cell-free DNA (cfDNA) are frequently observed in tumor patients.,Activating mutations in exon 4 (R183) and exon 5 (Q209) of GNAQ and GNA11 are almost exclusively found in uveal melanoma, thus providing a highly specific marker for the presence of circulating tumor DNA (ctDNA).,To establish a reliable... | 1 |
Avelumab is an anti-programmed cell death ligand 1 (PD-L1) antibody approved for treatment of Merkel cell carcinoma (MCC) and locally advanced or metastatic urothelial carcinoma.,It shares a similar side effect profile to other immune checkpoint inhibitors, including immune-related adverse reactions in the skin.,These ... | Currently, there is no established standard of care for patients with metastatic CSCC.,Based on the mechanisms of CSCC carcinogenesis has been postulated that these tumors may be amenable to PD-1/PD-L1 blockade.,This case illustrates a patient with CSCC with nodal involvement and pulmonary metastases, refractory to two... | 1 |
Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse.,Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel wit... | We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS.,We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK-ERK signaling.,This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibit... | 1 |
Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed.,In this work, the immune system of ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment out... | We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment.,Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) br... | 1 |
Tumour spheroids are common in vitro experimental models of avascular tumour growth.,Compared with traditional two-dimensional culture, tumour spheroids more closely mimic the avascular tumour microenvironment where spatial differences in nutrient availability strongly influence growth.,We show that spheroids initiated... | In vitro studies and mathematical models are now being widely used to study the underlying mechanisms driving the expansion of cell colonies.,This can improve our understanding of cancer formation and progression.,Although much progress has been made in terms of developing and analysing mathematical models, far less pr... | 1 |
Tissue-resident memory CD8+ T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors.,However, whether Trm cells cross-talk with dendritic cells (DCs) to support anti-tumor immunity remains unclear.,Here we show that antigen-specific activation of skin Trm cel... | Tumor cells evade the immune surveillance by up-regulating surface expression of PD-L1, which interacts with PD-1 on T cells to elicit the immune checkpoint response1,2.,Anti-PD-1 antibodies have shown remarkable promise in treating tumors, including metastatic melanoma2-4.,However, patient response rate is low4,5.,A b... | 1 |
There is an increasing global interest to support research areas that can assist in understanding disease and improving patient care.,The National Cancer Institute (NIH) has identified precision medicine-based approaches as key research strategies to expedite advances in cancer research.,The Cancer Moonshot program (ht... | Patient: Female, 50,Final Diagnosis: Adrenal insufficiency,Symptoms: Appetite loss • severe fatigue,Medication: -,Clinical Procedure: -,Specialty: Endocrinology and Metabolic,Unusual clinical course,Ipilimumab is a therapeutic human monoclonal antibody that targets the T-cell inhibitory molecule, cytotoxic T-lymphocyte... | 1 |
Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells.,However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy.,Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cyt... | Interaction between malignant cells and immune cells that reside within the tumor microenvironment (TME) modulate different aspects of tumor development and progression.,Recent works showed the importance of miRNA-containing extracellular vesicles in this crosstalk.,Interested in understanding the interplay between mel... | 1 |
The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment.,There are disparate views as to the pro- and anti-tumor ... | Selection of single antigen-specific B cells to identify their expressed antibodies is of considerable interest for evaluating human immune responses.,Here, we present a method to identify single antibody-expressing cells using antigen-conjugated fluorescent beads.,To establish this, we selected Folate Receptor alpha (... | 1 |
Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms.,After the publication of the first guidelines for ... | Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (L-CTCL) that arises from malignant clonally derived skin-homing CD4+ T cells.,Based on advancements in our understanding of the mechanisms underlying L-CTCL, boosting the suppressed immune response emerges as a promising strategy in SS... | 1 |
The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma.,We report long-term follow-up of c... | The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma.,We present final OS data from BRIM-3.,Patients were randomly assigned in a 1 : 1 ratio to receive vemurafe... | 1 |
Acquired resistance during BRAF inhibitor therapy remains a major challenge for melanoma treatment.,Accordingly, we evaluated the phenotypical and molecular changes of isogeneic human V600E BRAF-mutant melanoma cell line pairs pre- and post-treatment with vemurafenib.,Three treatment naïve lines were subjected to in vi... | Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge.,We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an ... | 1 |
The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression.,Clinical trials are in progress using MEK inhibitors following disease progression in patients receivi... | Oncogenic mutations in the serine/threonine kinase B-RAF are found in 50-70% of malignant melanomas1.,Pre-clinical studies have demonstrated that the B-RAFV600E mutation predicts a dependency on the mitogen activated protein kinase (MAPK) signaling cascade in melanoma1-5-an observation that has been validated by the su... | 1 |
Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse.,This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism.,Here, we examine how targeted th... | The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS) has recently become a focal point of cancer research.,However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the dise... | 1 |
Development of resistance to inhibitors of BRAF (BRAFi) and MEK (MEKi) remains a great challenge for targeted therapy in patients with BRAF-mutant melanoma.,Here, we explored the role of miRNAs in melanoma acquired resistance to BRAFi.,miRNA expression in two BRAF-mutant melanoma cell lines and their dabrafenib-resista... | It has been shown that the response of V600EBRAF melanoma cells to targeted therapeutics is affected by growth factors.,We have investigated the influence of three different growth factors, bFGF, EGF and HGF used either alone or in combination, on the response of V600EBRAF melanoma cell populations established from sur... | 1 |
The incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades.,Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial.,... | Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC).,In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) m... | 1 |
Since deterioration of the immune apparatus is closely associated with cancer, we examined the effect of aging on the growth and metastasis of intraocular melanomas in mice.,Murine B16LS9 melanoma cells were transplanted into the posterior compartment of the eye (vitreous chamber) and intraocular tumor growth and devel... | Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor-A (VEGF-A), was originally developed as an anti-tumor treatment.,In ocular oncology, it is being used to treat macular edema due to radiation retinopathy, but it may also be useful for the treatment of primary uveal melanoma (UM) or its ... | 1 |
N-acetyltransferase 10 (NAT10) has been considered a target for the treatment of human diseases such as cancer and laminopathies; however, its functional role in the biology of melanocytes is questionable.,Using a small molecule or small interfering RNA targeting NAT10, we examined the effect of NAT10 inhibition on mel... | Melanoma is a cancer with rising incidence and new therapeutics are needed.,For this, it is necessary to understand the molecular mechanisms of melanoma development and progression.,Melanoma differs from other cancers by its ability to produce the pigment melanin via melanogenesis; this biosynthesis is essentially regu... | 1 |
Activated RAS promotes dimerization of members of the RAF kinase family1-3.,ATP-competitive RAF inhibitors activate ERK signaling4-7 by transactivating RAF dimers4.,In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity.,This tumor-... | Oncogenic mutations in the serine/threonine kinase B-RAF are found in 50-70% of malignant melanomas1.,Pre-clinical studies have demonstrated that the B-RAFV600E mutation predicts a dependency on the mitogen activated protein kinase (MAPK) signaling cascade in melanoma1-5-an observation that has been validated by the su... | 1 |
Increased or decreased expression of LIF receptor (LIFr) has been reported in several human cancers, including skin cancer, but its role in melanoma is unknown.,In this study, we investigated the expression pattern of LIFr in melanoma and assessed its prognostic value.,Using tissue microarrays consisting of 441 melanom... | A cardinal feature of malignant melanoma is its metastatic propensity.,An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients.,In this study, we conducted global genomic character... | 1 |
Melanoma is an aggressive malignancy of melanocytes and most commonly arises in the skin.,In 2002, BRAF gene mutations were identified in melanoma, and this finding resulted in the development of several small-molecule molecular inhibitors that specifically targeted the BRAF V600E mutation.,The development of targeted ... | RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61.,Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melano... | 1 |
The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma.,The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response.,Directly injecting im... | One of the problems in antigen-specific cancer immunotherapy is the low density of the tumor antigen-derived peptide endogenously presented on tumor cell surface major histocompatibility complex class I molecules.,To overcome this, we are engaged in research on peptide intra-tumor injection to enhance tumor cell antige... | 1 |
Skin melanoma remains a highly prevalent and yet deadly form of cancer, with the exact degree of melanoma-associated mortality being strongly dependent upon the local tumor microenvironment.,The exact composition of stromal and immune cells within this microenvironmental region has the potential to profoundly impact me... | Effective management of melanoma depends heavily on early diagnosis.,When detected in early non-metastatic stages, melanoma is almost 100% curable by surgical resection, however when detected in late metastatic stages III and IV, 5-year survival rates drop to ~50% and 10-25%, respectively, due to limited efficacy of cu... | 1 |
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis.,In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab.,For avelumab-refractory patients, efficient and safe treatment options are lacking.,At three different sites in Germany, clini... | Merkel cell carcinoma (MCC) is a rare but clinically aggressive cancer with a high mortality rate.,In recent years, antibodies blocking the interactions among PD-1 and its ligands have generated durable tumor regressions in patients with advanced MCC.,However, there is a paucity of data regarding effective therapy for ... | 1 |
The aim of this study was to compare the efficacy and safety of interferon (IFN) combined with dacarbazine (DTIC) (experimental group) versus DTIC alone (control group) in cutaneous malignant melanoma.,After searching all available databases, eligible articles were identified and subjected to quality assessment.,Meta-a... | Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study.,In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed.,Thirty-six patients treatment-naïve advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously.,T... | 1 |
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