Pigment Cell & Melanoma Research最新文献

A novel approach to melanoma diagnosis—in vivo molecular skin fluorescence imaging (mSFI)—was developed to identify premalignant changes in the form of tissue remodeling related to melanoma development in humans by imaging the proximal microenvironment of lesions. The method was tested using a fluorescent peptide (ORL-1) which binds to αvβ3 integrin, a molecule associated with invasive melanoma development. A cut off score of 7 was established, differentiating melanomas from nonmelanoma nevi with 100% sensitivity, and 95.7% specificity, while identifying dysplastic nevi with the potential for melanoma development.

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture-based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co-occurred with KIT mutation and amplification. The most common pathways affected were the mitogen-activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression-free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32–19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22–15.30). Treatment with immune-checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01–0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs.

Intercellular communication is a cell-type and stimulus-dependent event driven not only by soluble factors but also by extracellular vesicles (EVs). EVs include vesicles of different size and origin that contain a myriad of molecules. Among them, small EVs (sEV; <200 nm) have been shown to modulate not just regional cell responses but also distant organ behavior. In cancer, distant organ modulation by sEVs has been associated to disease dissemination, which is one of the main concerns in melanoma. Description of broadly conserved alterations in sEV-contained molecules represents a strategy to identify key modifications in cellular communication as well as new disease biomarkers. Here, we characterize proteomes of cutaneous melanocyte and melanoma-derived sEVs to deepen on the landscape of normal and disease-related cell communication. Results reveal the presence of unique protein signatures for melanocytes and melanoma cells that reflect cellular transformation-related profound modifications. Melanocyte-derived sEVs are enriched in oxidative metabolism (e.g., aconitase 2, ACO2) or pigmentation (e.g., tyrosinase, TYR) related proteins while melanoma-derived sEVs reflect a generalized decrease in mature melanocytic markers (e.g., melanoma antigen recognized by T-cells 1, MART-1, also known as MLANA) and an increase in epithelial to mesenchymal transition (EMT)-related adhesion molecules such as tenascin C (TNC).

Dacarbazine (DTIC) and its oral counterpart temozolomide (TMZ) have been the most used agents in advanced malignant melanoma (MM) patients and they are still used routinely. The preferred first line treatment, immune checkpoint inhibitors (CPIs) might shape the tumor and the tumor microenvironment, possibly affecting the response to subsequent therapies. The aim of this study was to investigate the treatment effect of DTIC/TMZ in MM patients after CPI therapy in a consecutive patient cohort and through systematic literature review and meta-analysis. Thirty-five patients with advanced MM treated with DTIC/TMZ after previous CPI therapy in three Swedish regions between 2017 and 2021 were recognized and seven case series studies were identified through systematic database review. Pooled data from all 345 patients showed a median real-world progression-free survival (rwPFS) of 1.9 months and overall survival (OS) of 6.0 months. Three of these studies were included in a meta-analysis comparing DTIC/TMZ after CPI treatment, versus no previous immunotherapy, showing no statistically significant differences in rwPFS or OS but higher real-world response rate to chemotherapy for the prior-CPI treated group (Odds Ratio: 2.24; 95% Confidence Interval: 1.04–4.86). The current study supports consideration of DTIC/TMZ in later line of treatment in the immunotherapy era.

Differences in survival according to the pTERT mutation subtypes (−124C > T, −146C > T, and tandem −138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (−124C > T, −146C > T, and tandem −138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem −138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the −124C > T and the −138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29–0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37–0.97, p = .037), compared to the −146C > T mutation. Finally, the −124C > T appeared to be more associated with the presence of TILs (non-brisk) than the −146C > T (OR 0.6, CI 0.40–1.01, p = .05). These findings confirmed that the −124C > T and the tandem −138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the −124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem −138_139CC > TT mutations.

Melanoma is the most aggressive type of skin cancer and is responsible for the majority of deaths from skin cancer. Therapeutic advances in the last few decades, notably the development of novel targeted therapies and immunotherapies have significantly improved patient outcomes; nonetheless, these options remain limited due to the onset of resistance to treatment modalities and relapse. In this review, we focus on the available therapeutic options, their benefits, and limitations.

It has been 30 (!!) years since I began working on zebrafish pigment cells, as a postdoc in the laboratory of Prof. Christiane Nüsslein-Volhard. There, I participated in the first large-scale mutagenesis screen in zebrafish, focusing on pigment cell mutant phenotypes. The isolation of colourless, shady, parade and choker mutants allowed us (as a postdoc in Prof. Judith Eisen's laboratory, and then in my own laboratory at the University of Bath since 1997) to pursue my ambition to address long-standing problems in the neural crest field. Thus, we have studied how neural crest cells choose individual fates, resulting in our recent proposal of a new, and potentially unifying, model which we call Cyclical Fate Restriction, as well as addressing how pigment cell patterns are generated. A key feature of our work in the last 10 years has been the use of mathematical modelling approaches to clarify our biological models and to refine our interpretations. None of this would have been possible without a hugely talented group of laboratory members and other collaborators from around the world—it has been, and I am sure will continue to be, a pleasure and privilege to work with you all!

Breslow thickness, ulceration, and mitotic rate are well-known prognostic factors for sentinel lymph node (SLN) metastasis in cutaneous melanoma. We investigated risk factors, including especially the degree of pigmentation, for SLN metastasis in Korean melanoma patients. We enrolled 158, composed of Korean 107 acral and 51 non-acral melanoma patients who underwent SLN biopsy. Clinicopathologic features such as Breslow thickness, ulceration, mitotic rate, and the degree of pigmentation were evaluated. The recurrence-free survival (RFS) rate and date of recurrence were determined. Fifty-four patients (34.2%) had a positive SLN biopsy result. In a multivariate analysis, Breslow thickness (odds ratio [OR] 1.93; 95% confidence interval [CI], 1.12–3.47; p = .022) and heavy pigmentation (OR 13.14; 95% CI, 2.96–95.20, p = .002) were associated with SLN metastasis. Positive SLN patients had a higher rate of loco-regional and/or distant recurrence (hazard ratio 6.32; 95% CI, 3.39–11.79; p < .001). Heavy pigmentation was associated with poor RFS. Heavy pigmentation is an independent predictor of SLN metastasis in both acral and non-acral melanoma. Our results suggest the need for in-depth SLN evaluation of cutaneous melanoma patients with heavy pigmentation and provide clinicians with important information for determining patient prognosis.

Melanoma is an aggressive malignant tumor with a poor prognosis. Vemurafenib (PLX4032, vem) is applied to specifically treat BRAF V600E-mutated melanoma patients. However, prolonged usage of vem makes patients resistant to the drug and finally leads to clinical failure. We previously tested the combination regimen of tubulin inhibitor VERU-111 with vem, as well as USP14 selective inhibitor b-AP15 in combination with vem, both of which have showed profound therapeutic effects in overcoming vem resistance in vitro and in vivo. Most importantly, we discovered that vem-resistant melanoma cell lines highly expressed E3 ligase SKP2 and DUB enzyme USP14, and we have demonstrated that USP14 directly interacts and stabilizes SKP2, which contributes to vem resistance. These works give us a clue that USP14 might be a promising target to overcome vem resistance in melanoma. MitoCur-1 is a curcumin derivative, which was originally designed to specifically target tumor mitochondria inducing redox imbalance, thereby promoting tumor cell death. In this study, we have demonstrated that it can work as a novel USP14 inhibitor, and thus bears great potential in providing an anti-tumor effect and sensitizing vem-resistant cells by inducing ferroptosis in melanoma. Application of MitoCur-1 dramatically induces USP14 inhibition and inactivation of GPX4 enzyme, meanwhile, increases the depletion of GSH and decreases SLC7A11 expression level. As a result, ferrous iron-dependent lipid ROS accumulated in the cell, inducing ferroptosis, thus sensitizes the vem-resistant melanoma cell. Interestingly, overexpression of USP14 antagonized all the ferroptosis cascade events induced by MitoCur-1, therefore, we conclude that MitoCur-1 induces ferroptosis through inhibition of USP14. We believe that by inhibition of USP14, vem resistance can be reversed and will finally benefit melanoma patients in future.

The immune-modulating protein CD52 attenuates lymphocyte function and is associated with autoimmune disorders, for example, multiple sclerosis (MS). CD52 represents a therapeutic target in MS and chronic lymphocytic leukemia (CLL). Its expression has prognostic and predictive value in CLL and is prognostic in breast cancer. Its significance in melanoma is unclear. We analyzed CD52 mRNA expression data from tumor bulk tissues of N = 445 untreated melanoma patients from The Cancer Genome Atlas (TCGA) Research Network and of N = 121 melanoma patients undergoing anti-PD-1 immune checkpoint blockade (ICB) with regard to outcome (overall survival [OS], disease control [DC], and progression-free survival [PFS]), single-cell RNA-Seq data of N = 4645 cells from N = 19 melanoma tissues, and N = 15,457 cells from normal skin provided by N = 5 donors. Higher CD52 mRNA expression was associated with favorable OS (hazard ratio (HR) = 0.820, [95% CI 0.734–0.916], p < .001) in non-ICB-treated melanoma and with PFS (HR = 0.875, [95% CI 0.775–0.989], p = .033) and DC (p = .005) in ICB-treated melanoma. CD52 expression correlated significantly with distinct immune cell subsets and correlated negatively with immune checkpoint expression in T cells. Moreover, our results suggest CD52 expression by a certain type of tissue-resident macrophages. CD52 mRNA was expressed in a small subgroup (8%) of immune checkpoint coexpressing melanoma cells. CD52 expression is associated with features of ICB response in melanoma. Concomitant ICB and anti-CD52 treatment requires critical review.