Pigment Cell & Melanoma Research最新文献

{"title":"The MITF regulatory network in melanoma","authors":"Jagat S. Chauhan,&nbsp;Michael H?lzel,&nbsp;Jean-Philippe Lambert,&nbsp;Francesca M. Buffa,&nbsp;Colin R. Goding","doi":"10.1111/pcmr.13053","DOIUrl":"https://doi.org/10.1111/pcmr.13053","url":null,"abstract":"<p>Bidirectional interactions between plastic tumor cells and the microenvironment critically impact tumor evolution and metastatic dissemination by enabling cancer cells to adapt to microenvironmental stresses by switching phenotype. In melanoma, a key determinant of phenotypic identity is the microphthalmia-associated transcription factor MITF that promotes proliferation, suppresses senescence, and anticorrelates with immune infiltration and therapy resistance. What determines whether MITF can activate or repress genes associated with specific phenotypes, or how signaling regulating MITF might impact immune infiltration is poorly understood. Here, we find that MITF binding to genes associated with high MITF is via classical E/M-box motifs, but genes downregulated when MITF is high contain FOS/JUN/AP1/ATF3 sites. Significantly, the repertoire of MITF-interacting factors identified here includes JUN and ATF3 as well as many previously unidentified interactors. As high AP1 activity is a hallmark of MITF^Low, invasive, slow-cycling, therapy resistant cells, the ability of MITF to repress AP1-regulated genes provides an insight into how MITF establishes and maintains a pro-proliferative phenotype. Moreover, although β-catenin has been linked to immune exclusion, many Hallmark β-catenin signaling genes are associated with immune infiltration. Instead, low MITF together with Notch signaling is linked to immune infiltration in both mouse and human melanoma tumors.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 5","pages":"517-533"},"PeriodicalIF":4.3,"publicationDate":"2022-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5878914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-dimensional imaging for the analysis of human epidermal melanocytes","authors":"Dai Hyun Kim,&nbsp;Se Jeong Lee,&nbsp;Soo Hong Seo,&nbsp;Hyo Hyun Ahn,&nbsp;Byung-Jo Kim,&nbsp;Woong Sun,&nbsp;Im Joo Rhyu","doi":"10.1111/pcmr.13051","DOIUrl":"https://doi.org/10.1111/pcmr.13051","url":null,"abstract":"<p>Three-dimensional (3-D) analysis of human epidermal melanocytes is required for deeper understanding of melanocytic disorders. The purpose of this study was to standardize 3-D imaging and quantification for the evaluation of epidermal melanocytes. The epidermal specimen was obtained using the suction blister method from a patient with melanocytic nevus on the forearm skin. Cutaneous ACT-PRESTO, the tissue-clearing and labeling technique, was subsequently performed. With the 3-D image analysis program, morphological reconstruction and quantification of selected perilesional and melanocytic nevus areas were possible. The region of melanocytic nevus showed higher numbers of total melanocytic dendrites and similar numbers of cell bodies compared with perilesional area. In addition, the mean area and volume of cell bodies increased in the melanocytic nevus area compared with the results in the perilesional area. The 3-D evaluation method of human epidermal melanocytes can be applied to investigate novel pathologies related to hyper- or hypo-pigmentary disorders.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 5","pages":"534-538"},"PeriodicalIF":4.3,"publicationDate":"2022-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5852757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic properties via MAPK signaling of the SOX5-RAF1 fusion gene identified in a wild-type NRAS/BRAF giant congenital nevus","authors":"Antònia Vinyals,&nbsp;Josep R. Ferreres,&nbsp;Neus Calbet-Llopart,&nbsp;Raquel Ramos,&nbsp;Gemma Tell-Martí,&nbsp;Cristina Carrera,&nbsp;Joaquim Marcoval,&nbsp;Susana Puig,&nbsp;Josep Malvehy,&nbsp;Joan Anton Puig-Butillé,&nbsp;àngels Fabra","doi":"10.1111/pcmr.13044","DOIUrl":"https://doi.org/10.1111/pcmr.13044","url":null,"abstract":"<p>We recently reported an <i>RAF</i> rearrangement without <i>NRAS</i> or <i>BRAF</i> mutations in lesions from Giant Congenital Melanocytic Nevi (CMN). The new gene fusion involves the 5′-end of the promoter-containing N terminus of the <i>SOX5</i> gene fused to exons 7–16 of the 3′-end of <i>RAF1</i> gene leading to a <i>SOX5-RAF1</i> fusion transcript which loses the auto-inhibitory CR1 domain but retains the complete in-frame coding sequence for the C-Terminal kinase domain of the <i>RAF1</i>. Stable expression of <i>SOX5-RAF1</i> fusion induced growth factor-independent cell growth in murine hematopoietic Ba/F3 cells and melan-a immortalized melanocytes. Besides, it led to the transformation of both Ba/F3 and NIH 3T3 cells as revealed by colony formation assays. Furthermore, its expression results in MAPK activation assessed by increased levels of p-ERK protein in the cytosol of transduced cells. Treatment with Sorafenib and UO126 inhibited proliferation of Ba/F3-SOX5-RAF1 cells in the absence of IL3 but not the PLX 4720, a specific inhibitor of BRAF. Moreover, the tumorigenic and metastatic capacities of SOX5-RAF1 were assessed in vivo. These results indicate that <i>SOX5-RAF1</i>, a driver event for CMN development, has oncogenic capacity. Thus, sequencing of CMN transcriptomes may lead to the identification of this druggable fusion and interfere with the progression toward melanoma.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 4","pages":"450-460"},"PeriodicalIF":4.3,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5763410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and functional assays of single-nucleotide variants of opsins genes in melanocytic tumors","authors":"Wei Zhang,&nbsp;Wen Zeng,&nbsp;Jianglong Feng,&nbsp;Pinhao Li,&nbsp;Yu Wang,&nbsp;Hongguang Lu","doi":"10.1111/pcmr.13043","DOIUrl":"https://doi.org/10.1111/pcmr.13043","url":null,"abstract":"<p>Epidermal melanocytes sense solar light via the opsin-coupled signaling pathway which is involved in a range of biological functions, including regulating pigmentation, proliferation, apoptosis, and tumorigenesis. However, it remains unclear whether there are genetic variants within these opsins that affect opsin protein structure and function, and further melanocyte biological behaviors. Here, we examined single-nucleotide variants (SNVs) of five opsin (<i>RGR, OPN1SW, OPN2, OPN4, and OPN5</i>) genes in MM (malignant melanoma; <i>n</i> = 76) and MN (melanocytic nevi; <i>n</i> = 157), using next-generation sequencing. The effects of these pathogenic single-nucleotide variants (SNVs) on opsin structure and function were further investigated using molecular dynamics (MD) simulations, dynamic cross-correlation (DCC), and site-directed mutagenesis. In total, 107 SNV variants were identified. Of these variants, 14 nonsynonymous SNVs (nsSNVs) of opsin genes were detected, including three mutations in the RGR gene, three mutations in the OPN1SW gene, two mutations in the OPN2 gene, and six mutations in the OPN4 gene. The effect of these missense mutations on opsin function was then assessed using eight prediction tools to estimate the potential impact of an amino acid substitution. The impact of each nsSNV was investigated using MD simulations and DCC analysis. Furthermore, we performed in vitro fluorescence calcium imaging to assess the functional properties of nsSNV proteins using a site-directed mutagenesis method. Taken together, these results revealed that p.A103V (RGR), p.T167I (RGR), p.G141S (OPN1SW), p.R144C (OPN1SW), and p.S231F (OPN4) had more deleterious effects on protein structure and function among the 14 nsSNVs. Opsin gene alterations showed the low frequency of missense mutations in melanocytic tumors, and although rare, some mutations in these opsin genes disrupt the canonical function of opsin. Our findings provide new insight into the role of opsin variants in the loss of function.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 4","pages":"436-449"},"PeriodicalIF":4.3,"publicationDate":"2022-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6193855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma","authors":"Pui Ying Chan,&nbsp;Melissa M. Phillips,&nbsp;Stephen Ellis,&nbsp;Amanda Johnston,&nbsp;Xiaoxing Feng,&nbsp;Amit Arora,&nbsp;Gordon Hay,&nbsp;Victoria M. L. Cohen,&nbsp;Mandeep S. Sagoo,&nbsp;John S. Bomalaski,&nbsp;Michael T. Sheaff,&nbsp;Peter W. Szlosarek","doi":"10.1111/pcmr.13042","DOIUrl":"https://doi.org/10.1111/pcmr.13042","url":null,"abstract":"<p>Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase <b>(</b>ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m²) and Cis (75 mg/m²) every 3 weeks plus weekly intramuscular ADI (36 mg/m²), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1-deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression-free survival of 3.0 months (range, 1.3–8.1) and a median overall survival of 11.5 months (range, 3.2–36.9). Despite anti-ADI-PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re-expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti-metabolite strategies.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 4","pages":"461-470"},"PeriodicalIF":4.3,"publicationDate":"2022-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6028807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fearful Temperament, Catastrophizing, and Internalizing Symptoms in Clinically Anxious Youth.","authors":"Haley E Conroy Busch, Andres G Viana, Elizabeth M Raines, Erika S Trent, Michael J Zvolensky, Eric A Storch","doi":"10.1891/JCP-2021-0022","DOIUrl":"10.1891/JCP-2021-0022","url":null,"abstract":"<p><p>A fearful temperament in childhood is associated with child internalizing symptoms. However, the cognitive mechanisms explaining this association are poorly understood. We examined the effects of child fearful temperament on child internalizing symptoms and the underlying role of catastrophizing cognitions among clinically anxious youth. Children (<i>N</i> = 105; <i>M</i> _age = 10.09 years, <i>SD</i> = 1.22; 56.7% female; 62% ethnic minority) completed a diagnostic interview; self-report measures of temperament, catastrophizing, and internalizing symptoms; and behaviorally-indexed measures of catastrophizing and anxiety. Indirect effects were found for child fearful temperament on child self-reported internalizing symptoms by way of self-reported (but not behaviorally-indexed) catastrophizing cognitions. Models predicting <i>behaviorally-indexed</i> child anxiety were not significant. Our findings suggest that targeting fearful temperament during childhood before catastrophizing cognitions develop may have clinical utility. Likewise, among children temperamentally at-risk, addressing catastrophic cognitions may prevent later internalizing psychopathology.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"27 2","pages":""},"PeriodicalIF":0.7,"publicationDate":"2022-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41269767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein-based classification of melanoma differentiation subtypes","authors":"Su Yin Lim,&nbsp;Bernadette Pedersen,&nbsp;Helen Rizos","doi":"10.1111/pcmr.13041","DOIUrl":"https://doi.org/10.1111/pcmr.13041","url":null,"abstract":"","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 4","pages":"471-473"},"PeriodicalIF":4.3,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5766833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consideration of possible effects of vitamin D on established cancer, with reference to malignant melanoma","authors":"Peter E. Hutchinson,&nbsp;James H. Pringle","doi":"10.1111/pcmr.13040","DOIUrl":"https://doi.org/10.1111/pcmr.13040","url":null,"abstract":"<p>Epidemiological studies indicate that Vitamin D has a beneficial, inhibitory effect on cancer development and subsequent progression, including melanoma (MM), and favourable MM outcome has been reported as directly related to vitamin D₃ status, assessed by serum 25-hydroxyvitamin D₃ (25[OH]D₃) levels taken at diagnosis. It has been recommended that MM patients with deficient levels of 25(OH)D₃ be given vitamin D₃. We examine possible beneficial or detrimental effects of treating established cancer with vitamin D₃. We consider the likely biological determinants of cancer outcome, the reported effects of vitamin D₃ on these in both cancerous and non-cancerous settings, and how the effect of vitamin D₃ might change depending on the integrity of tumour vitamin D receptor (VDR) signalling. We would argue that the effect of defective tumour VDR signalling could result in loss of suppression of growth, reduction of anti-tumour immunity, with potential antagonism of the elimination phase and enhancement of the escape phase of tumour immunoediting, possibly increased angiogenesis but continued suppression of inflammation. In animal models, having defective VDR signalling, vitamin D₃ administration decreased survival and increased metastases. Comparable studies in man are lacking but in advanced disease, a likely marker of defective VDR signalling, studies have shown modest or no improvement in outcome with some evidence of worsening. Work is needed in assessing the integrity of tumour VDR signalling and the safety of vitamin D₃ supplementation when defective.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 4","pages":"408-424"},"PeriodicalIF":4.3,"publicationDate":"2022-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5736696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconstructed human pigmented skin/epidermis models achieve epidermal pigmentation through melanocore transfer","authors":"Michael J. Hall,&nbsp;Sara Lopes-Ventura,&nbsp;Matilde V. Neto,&nbsp;Jo?o Charneca,&nbsp;Patricia Zoio,&nbsp;Miguel C. Seabra,&nbsp;Abel Oliva,&nbsp;Duarte C. Barral","doi":"10.1111/pcmr.13039","DOIUrl":"https://doi.org/10.1111/pcmr.13039","url":null,"abstract":"<p>The skin acts as a barrier to environmental insults and provides many vital functions. One of these is to shield DNA from harmful ultraviolet radiation, which is achieved by skin pigmentation arising as melanin is produced and dispersed within the epidermal layer. This is a crucial defence against DNA damage, photo-ageing and skin cancer. The mechanisms and regulation of melanogenesis and melanin transfer involve extensive crosstalk between melanocytes and keratinocytes in the epidermis, as well as fibroblasts in the dermal layer. Although the predominant mechanism of melanin transfer continues to be debated and several plausible models have been proposed, we and others previously provided evidence for a coupled exo/phagocytosis model. Herein, we performed histology and immunohistochemistry analyses and demonstrated that a newly developed full-thickness three-dimensional reconstructed human pigmented skin model and an epidermis-only model exhibit dispersed pigment throughout keratinocytes in the epidermis. Transmission electron microscopy revealed melanocores between melanocytes and keratinocytes, suggesting that melanin is transferred through coupled exocytosis/phagocytosis of the melanosome core, or melanocore, similar to our previous observations in human skin biopsies. We, therefore, present evidence that our <i>in vitro</i> models of pigmented human skin show epidermal pigmentation comparable to human skin. These findings have a high value for studies of skin pigmentation mechanisms and pigmentary disorders, whilst reducing the reliance on animal models and human skin biopsies.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 4","pages":"425-435"},"PeriodicalIF":4.3,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5838575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Focused review on the pathophysiology of post-inflammatory hyperpigmentation","authors":"Jalal Maghfour,&nbsp;Jadesola Olayinka,&nbsp;Iltefat H. Hamzavi,&nbsp;Tasneem F. Mohammad","doi":"10.1111/pcmr.13038","DOIUrl":"https://doi.org/10.1111/pcmr.13038","url":null,"abstract":"<p>Post-inflammatory hyperpigmentation (PIH) is one of the most common disorders of acquired hyperpigmentation. It often develops following cutaneous inflammation and is triggered by various stimuli, from inflammatory and autoimmune conditions to iatrogenic causes and mechanical injuries. While it is well established that an increase in melanin production and distribution within the epidermis and dermis is a hallmark feature of this condition, the exact mechanisms underlying PIH are not completely understood. This article aims to review the current evidence on the pathophysiology of PIH as the cellular and molecular mechanism of PIH represents a promising avenue for the development of novel, targeted therapies.</p>","PeriodicalId":219,"journal":{"name":"Pigment Cell & Melanoma Research","volume":"35 3","pages":"320-327"},"PeriodicalIF":4.3,"publicationDate":"2022-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcmr.13038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6242770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}