Cutaneous melanoma is the most lethal skin cancer, and risk is strongly shaped by pigmentary phenotype. The red-hair color phenotype, marked by red hair, fair skin, freckling, and poor tanning, carries elevated melanoma risk driven largely by loss-of-function variants in the melanocortin 1 receptor gene (MC1R). This risk is not explained by reduced ultraviolet protection alone. Impaired MC1R signaling shifts melanogenesis from photoprotective eumelanin toward pheomelanin, a pigment associated with oxidative stress and partly ultraviolet-independent melanomagenesis. MC1R may also influence melanoma susceptibility through pigment-independent effects on DNA damage responses, repair signaling, and genomic stability. These mechanisms support investigation of MC1R genotype, visible phenotype, nevus burden, pigment chemistry, and imaging-derived lesion metrics as complementary tools for risk stratification. Diagnosis is also distinctive in this population. Amelanotic and hypomelanotic melanomas are associated with the red-hair color phenotype, and their low pigmentary contrast may delay recognition and contribute to diagnosis at a more advanced stage. This review integrates genetic, molecular, biomarker, diagnostic, and therapeutic literature specific to red-haired populations. We argue that elevated biological susceptibility and diagnostic difficulty compound one another, and we outline priorities for MC1R-informed surveillance, imaging adapted to pigment-poor disease, pharmacologic modulation of MC1R-related pathways, and prospective risk models integrating genotype, phenotype, nevus burden, pigment biology, and imaging.

Misfolding of aggregation-prone proteins underpins diseases known as proteinopathies. One of these proteins, alpha-synuclein, is a component of aggregates in neurodegenerative conditions such as Parkinson's disease. The melanosomal protein PMEL, which forms physiologic amyloid scaffold structures on which melanin is organized in melanosomes, similarly ectopically accumulates in the dermis in many forms of cutaneous hyperpigmentation. Here, we demonstrate in a wide range of common clinical pigmentary disorders, as well as in primary melanocyte and mouse models examined by molecular, proteomic, and electron microscopic tools, that melanocytic alpha-synuclein is a prominent component of intracellular protein aggregates bound to similar proteins as in Parkinson's disease, as well as melanized extracellular protein deposits. Using the Real Time Quaking-Induced Conversion Assay (RT-QuIC), we demonstrate that UV induces misfolded melanosomal proteins to self-propagate, augmenting this pathology in prion-like fashion. CUT&RUN chromatin profiling and single-cell RNA-seq demonstrate that melanocytes utilize microphthalmia-associated transcription factor (MITF)-regulated autophagy to counteract protein aggregation, identifying aggregate removal as a core function of tanning. In contrast to extracellular aggregation, impaired intracellular aggregate removal contributes to melanocyte senescence, which conversely exacerbates chronic hypopigmentation and photoaging-related discoloration. These findings identify melanosomal proteinopathy as a common contributor to melanocyte dysfunction and suggest aggregate-focused management approaches.

Cutaneous melanoma is an aggressive form of skin cancer derived from skin melanocytes and is associated with significant morbidity and mortality. A significant fraction of melanomas are associated with precursor lesions, benign clonal proliferations of melanocytes called nevi. Nevi can be either congenital or acquired later in life. Identical oncogenic driver mutations are found in benign nevi and melanoma. While much progress has been made in our understanding of nevus formation and the molecular steps required for transformation of nevi into melanoma, the clinical diagnosis of benign versus malignant lesions remains challenging.

One effort to combat the rising incidence of malignant melanoma is focused on early detection by the clinical and dermoscopic screening of melanocytic nevi. However, the interaction between nevi, which are congenital or acquired benign melanocytic proliferations, and melanoma is still enigmatic. On the one hand, the majority of melanomas are thought to form de novo, as only a third of primary melanomas are associated with a histologically identifiable nevus precursor. On the other hand, an increased number of melanocytic nevi is a strong risk factor for developing melanoma, including melanomas that do not derive from nevi. The formation of nevi is modulated by diverse factors, including pigmentation, genetic risk factors, and environmental sun exposure. While the molecular alterations that occur during the progression of a nevus to melanoma have been well characterized, many unanswered questions remain surrounding the process of nevus to melanoma evolution. In this review, we discuss clinical, histological, molecular, and genetic factors that influence nevus formation and progression to melanoma.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth(1,2). Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

Melanoma skin cancer is derived from skin melanocytes and has a high risk of metastatic spread. The era of molecular genetics and next-generation sequencing has uncovered the role of oncogenic BRAFV600E mutations in many melanomas, validated the role of ultraviolet-induced DNA mutations in melanoma formation, and uncovered many of the molecular events that occur during melanoma development. Targeted therapies and immunotherapy have dramatically improved outcomes and provided an increased rate of cure for metastatic melanoma. This article reviews the formation of melanoma, the molecular events involved in melanoma growth and metastasis, and the biology underlying resistance to melanoma therapies.

Resistance to targeted therapy and immunotherapy remains a major obstacle in improving care for patients with advanced melanoma. MicroRNAs play important roles in regulating gene networks involved in disease progression and resistance to therapy in cancers such as melanoma. MicroRNA miR-211 contributes to melanocyte and melanoma biology and has been implicated in targeted therapy resistance. Lee et al. (2020) report a novel mechanism by which miR-211 promotes resistance to BRAF(V600E) inhibitor therapy via the upregulation of the extracellular signale-regulated kinase 5 signaling pathway.

Pyogenic granulomas (PG) are benign vascular proliferations of the skin and mucous membranes that are traditionally treated by surgical excision, electrocautery, cryotherapy, or laser therapy.1 Because procedural treatments can be costly, painful, inconvenient, leave a scar, and require a live patient intervention, alternate options are of investigational interest. We present two children with PGs who were successfully treated with topical clobetasol 0.05% ointment under occlusion. In our first case, a 15-year-old boy with autism spectrum disorder and two facial PGs underwent biopsy and was unable to tolerate further procedural treatment; after applying topical clobetasol nightly for three months, the lesions reduced in erythema and size. The second patient, a 3-year-old girl with a clinically diagnosed facial PG, used topical clobetasol daily for eight weeks, resulting in significant PG regression at 6 weeks and complete involution 10 months later. For both patients, there were no adverse responses noted following consistent topical application between 8 weeks to 3 months. Our cases demonstrate that topical potent corticosteroid applied under occlusion may offer a safe, effective, and noninvasive therapeutic option for intact PGs in children. The vasoconstrictive properties of topical steroids in addition to possible angiogenic factor inhibition may contribute to the pathophysiologic mechanism behind clinical response.2 In addition to pediatric patients, topical steroids may provide a PG treatment alternative for patients unable to tolerate procedures and/or those seen virtually. 1. Lin RL , Janniger CK. Pyogenic granuloma. Cutis 2004;74:229-33. 2. Greenberger S, Boscolo E, Adini I, Mulliken JB , Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 2010;362:1005-13.

Pyogenic granulomas are benign vascular proliferations of the skin and mucous membranes that tend to bleed easily. They typically require procedural treatments that can be difficult for patients with intellectual disabilities or behavioral concerns to tolerate. In our practice, we have found the use of topical clobetasol to be effective to induce regression of cutaneous pyogenic granulomas. We present here a case of an adolescent patient with autism and two bleeding pyogenic granulomas who poorly tolerated a biopsy of the first lesion and could not tolerate subsequent procedures. Topical therapy with clobetasol effectively managed the second pyogenic granuloma, an approach representative of a noninvasive practice utilized in our clinic.

Skin pigmentation is a result of melanin produced by melanocytes in the epidermis. Melanocyte activity, along with the type and distribution of melanins, is the main driver for diversity of skin pigmentation. Dark melanin acts to protect against the deleterious effects of ultraviolet (UV) radiation, including photo-aging and skin cancer formation. In turn, UV radiation activates skin melanocytes to induce further pigmentation (i.e., "tanning pathway"). The well-characterized MSH/MC1R-cAMP-MITF pathway regulates UV-induced melanization. Pharmacologic activation of this pathway ("sunless tanning") represents a potential strategy for skin cancer prevention, particularly in those with light skin or the "red hair" phenotype who tan poorly after UV exposure due to MC1R inactivating polymorphisms. Skin hyperpigmentation can also occur as a result of inflammatory processes and dermatological disorders such as melasma. While primarily of cosmetic concern, these conditions can dramatically impact quality of life of affected patients. Several topical agents are utilized to treat skin pigmentation disorders. Here, we review melanogenesis induced by UV exposure and the agents that target this pathway.

In contrast to an established role for tissue resident memory T cells (TRM) formation and protection to viral infections, formation and activity during cancer formation, including skin cancers is unknown. Here, we compare tumor-infiltrating lymphocytes (TILs) composition, circulating T cells, and tumor adjacent and non-adjacent skin T cells during a slow spontaneous model of melanoma formation (42-52 days). We tested BrafV600E, CDKN2A-/-, PTEN-/- mice to model the 40-50% of melanoma patients harboring Braf mutations (>90% BrafV600E). A majority of tumor infiltrating CD4+ (70%) and CD8+ (90%) of T lymphocytes express phenotypic markers for tissue residence such as CD69+ CD103+/-. We observed PD-1 expression on multiple T cell populations in the tumor microenvironment including CD3+ FoxP3+ CD25+ Treg. A significant accumulation of CD4+CD44+CD62L+KLRG1+CCR7low T cells was observed in the tumor draining LNs of mice with tumors, but not controls. Mice with tumors demonstrated higher T cell numbers in adjacent and non-adjacent skin. In contrast to TILs, PD-1 expression levels in tamoxifen-induced tumor mice were found to be similar to isotype and levels on control mice in the skin draining lymph nodes, tumor-adjacent and tumor non-adjacent skin, and spleen, suggesting that in this model PD-1 expression is largely restricted to tumor infiltrating lymphocytes. Collectively, these data suggest that in conditions favoring slow progressive spontaneous melanoma, TILs share phenotypic properties of TRM and are amongst the highest PD-1 expressing TILs. Subsequent work will further interrogate the cutaneous immune response to spontaneous melanoma skin cancer and the role of PD-1.

In the United States, the incidence and mortality rates for Merkel cell carcinoma (MCC) have more than tripled in the last 2 decades.1 The main risk factors involved in MCC pathogenesis include ultraviolet light exposure, immunosuppression, and Merkel cell polyomavirus (MCpV).2 The most common sites include the head and neck (53%) and extremities (34%–35%), with trunk and mucosal surfaces representing less than 10% of cases.3

Evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, may reduce the risk of Alzheimer's disease (AD). Statin action in patients with AD, as in those with heart disease, is likely to be at least partly independent of the effects of statins on cholesterol. Statins can alter cellular signaling and protein trafficking through inhibition of isoprenylation of Rho, Cdc42, and Rab family GTPases. The effects of statins on protein isoprenylation in vivo, particularly in the central nervous system, are poorly studied. We utilized two-dimensional gel electrophoresis approaches to directly monitor the levels of isoprenylated and non-isoprenylated forms of Rho and Rab family GTPases. We report that simvastatin significantly inhibits RhoA and Rab4, and Rab6 isoprenylation at doses as low as 50nM in vitro. We also provide the first in vivo evidence that statins inhibit the isoprenylation of RhoA in the brains of rats and RhoA, Cdc42, and H-Ras in the brains of mice treated with clinically relevant doses of simvastatin.

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 homologously recombined at the ROSA locus (ROSAsT), allowing Cre-mediated, conditional MCV sT expression. Standard tamoxifen (TMX) administration to adult UbcCreERT2; ROSAsT mice, in which Cre is ubiquitously expressed, resulted in MCV sT expression in multiple organs that was uniformly lethal within 5 days. Conversely, most adult UbcCreERT2; ROSAsT mice survived low-dose tamoxifen administration but developed ear lobe dermal hyperkeratosis and hypergranulosis. Simultaneous MCV sT expression and conditional homozygous p53 deletion generated multi-focal, poorly-differentiated, highly anaplastic tumors in the spleens and livers of mice after 60 days of TMX treatment. Mouse embryonic fibroblasts from these mice induced to express MCV sT exhibited anchorage-independent cell growth. To examine Merkel cell pathology, MCV sT expression was also induced during mid-embryogenesis in Merkel cells of Atoh1CreERT2/+; ROSAsT mice, which lead to significantly increased Merkel cell numbers in touch domes at late embryonic ages that normalized postnatally. Tamoxifen administration to adult Atoh1CreERT2/+; ROSAsT and Atoh1CreERT2/+; ROSAsT; p53flox/flox mice had no effects on Merkel cell numbers and did not induce tumor formation. Taken together, these results show that MCV sT stimulates progenitor Merkel cell proliferation in embryonic mice and is a bona fide viral oncoprotein that induces full cancer cell transformation in the p53-null setting.

Merkel cells are mechanosensitive skin cells whose production requires the basic helix-loop-helix transcription factor Atoh1. We induced ectopic Atoh1 expression in the skin of transgenic mice to determine whether Atoh1 was sufficient to create additional Merkel cells. In embryos, ectopic Atoh1 expression drove ectopic expression of the Merkel cell marker keratin 8 (K8) throughout the epidermis. Epidermal Atoh1 induction in adolescent mice similarly drove widespread K8 expression in glabrous skin of the paws, but in the whisker pads and body skin ectopic K8+ cells were confined to hair follicles and absent from interfollicular regions. Ectopic K8+ cells acquired several characteristics of mature Merkel cells in a time frame similar to that seen during postnatal development of normal Merkel cells. Although ectopic K8+ cell numbers decreased over time, small numbers of these cells remained in deep regions of body skin hair follicles at 3 months post-induction. In adult mice, greater numbers of ectopic K8+ cells were created by Atoh1 induction during anagen versus telogen and following disruption of Notch signaling by conditional deletion of Rbpj in the epidermis. Our data demonstrate that Atoh1 expression is sufficient to produce new Merkel cells in the epidermis, that epidermal cell competency to respond to Atoh1 varies by skin location, developmental age and hair cycle stage, and that the Notch pathway plays a key role in limiting epidermal cell competency to respond to Atoh1 expression.

Nervous system involvement in psoriasis pathogenesis is supported by increases in nerve fiber numbers and neuropeptides in psoriatic skin and by reports detailing spontaneous plaque remission following nerve injury. Using the KC-Tie2 psoriasiform mouse model, we investigated the mechanisms by which nerve injury leads to inflammatory skin disease remission. Cutaneous nerves innervating dorsal skin of KC-Tie2 animals were surgically axotomized and beginning 1 day after denervation, CD11c(+) cell numbers decreased by 40% followed by a 30% improvement in acanthosis at 7 days and a 30% decrease in CD4(+) T-cell numbers by 10 days. Restoration of substance P (SP) signaling in denervated KC-Tie2 skin prevented decreases in CD11c(+) and CD4(+) cells, but had no effect on acanthosis; restoration of calcitonin gene-related peptide (CGRP) signaling reversed the improvement in acanthosis and prevented denervated-mediated decreases in CD4(+) cells. Under innervated conditions, small-molecule inhibition of SP in KC-Tie2 animals resulted in similar decreases to those observed following surgical denervation for cutaneous CD11c(+) and CD4(+) cell numbers; whereas small-molecule inhibition of CGRP resulted in significant reductions in CD4(+) cell numbers and acanthosis. These data demonstrate that sensory nerve-derived peptides mediate psoriasiform dendritic cell and T-cell infiltration and acanthosis and introduce targeting nerve-immunocyte/KC interactions as potential psoriasis therapeutic treatment strategies.