Pigment Cell & Melanoma Research最新文献

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.

The human red hair color (RHC) trait is caused by increased pheomelanin (red-yellow) and reduced eumelanin (black-brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While MC1R variants have been established as causative of RHC and are a well-defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility. Here, we use single-cell RNA sequencing (scRNA-seq) of melanocytes isolated from RHC mouse models to define a MC1R-inhibited Gene Signature (MiGS) comprising a large set of previously unidentified genes which may be implicated in melanogenesis and oncogenic transformation. We show that one of the candidate MiGS genes, TBX3, a well-known anti-senescence transcription factor implicated in melanoma progression, binds both E-box and T-box elements to regulate genes associated with melanogenesis and senescence bypass. Our results provide key insights into further mechanisms by which melanocytes with reduced MC1R signaling may regulate pigmentation and offer new candidates of study toward understanding how individuals with the RHC phenotype are predisposed to melanoma.

Epidermal melanocytes are continuously exposed to sunlight-induced reactive oxygen species (ROS) and oxidative stress generated during the synthesis of melanin. Therefore, they have developed mechanisms that maintain normal redox homeostasis. Cytoglobin (CYGB), a ubiquitously expressed intracellular iron hexacoordinated globin, exhibits antioxidant activity and regulates the redox state of mammalian cells through its activities as peroxidase and nitric oxide (NO) dioxygenase. We postulated that CYGB functions in the melanogenic process as a regulator that maintains oxidative stress within a physiological level. This was examined by characterizing normal human melanocytes with the knockdown (KD) of CYGB using morphological and molecular biological criteria. CYGB-KD cells were larger, had more dendrites, and generated more melanin granules in the advanced stages of melanogenesis than control cells. The expression levels of major melanogenesis-associated genes and proteins were higher in CYGB-KD melanocytes than in wild type (WT) cells. As expected, CYGB-KD melanocytes generated more ROS and NO than WT cells. In conclusion, CYGB physiologically contributes to maintaining redox homeostasis in the melanogenic activity of normal melanocytes by controlling the intracellular levels of ROS and NO.

It has been an honor and privilege to serve as Editor-in-Chief of Pigment Cell & Melanoma Research. This is a unique journal in many respects. It is the official journal of two scientific societies. Established first as Pigment Cell Research under the auspices of the Federation of Pigment Cell Societies, later became Pigment Cell & Melanoma Research by welcoming Society for Melanoma Research to be equal partner. With this merger, the scope of manuscripts now published span the widest range of topics that include chemistry of melanin, vertebrate pigmentation, and pigmentary diseases to melanoma biology and clinical trials. I enjoyed the front row view of this expansive landscape and made every effort to make each issue reflect the scope of the journal.

I have many individuals to thank for making it a worthwhile journey. Foremost, the Associate Editors, who often shouldered equal burden, colleagues, who stepped up every time they were asked to review manuscripts, and the journal staff at Wiley, who supported the workflow. I will miss the opportunity and the privilege of being the first to glimpse research coming out from laboratories across the world. I will miss the opportunity to read the insightful reviews from researchers I hold in high esteem.

Six years ago, when I accepted to serve as Editor-in-Chief of this journal, there was some unspoken skepticism about the viability of the journal in its current form in the fast-changing landscape of journal publishing. As an optimist, I brushed aside such skepticism. Even after 6 years in the trenches, including the difficult period of COVID-19 pandemic, I remain optimistic about the future of this unique journal. There are and will be many challenges to overcome. A journal is only as good as the quality of manuscripts it receives and the peer reviews of those manuscripts. Therefore, it is my sincere hope that the members of the pigment cell and melanoma community, bound together by our interest in this fascinating entity we call “melanocyte”, choose this journal as their first choice to submit and publish their best work and be ready and willing to serve as reviewers. More than anything else, this will be a true test of the commitment of members of this community to the success of this journal. As a member of both pigment cell and melanoma societies, I commit to continue to do my part.