Melanocyte Migration Research Articles

1217 Nicotinic acid inhibit the melanocyte migration of melanoma

Melanoma is currently the most highest mortality rate of skin tumors, but the treatment of melanoma is limited.The global incidence of melanoma continues to increase every year. This tumor has highly aggressive and metastatic potential.Therefore, inhibition of tumor cell invasion may provide an effective therapy for melanoma. Here we report the Nicotinamide ,also named nicotinic acid (NA) ,which can inhibits melanoma cell invasion in vitro. Treatment of the B16-F10 cell with NA in vitro results in reduced invasion, and has concentration depends on the relationship,we found that inhibition of cell migration was most obvious when the concentration of niacin was 10 μM. At the molecular level, transcription of the adherens junction protein E-cadherin is increased, leading to accumulation of E-cadherin protein at the cell-cell boundary.The expression of transcription factor snail2 and twist which can promote tumor cell migration are significantly decreased.And we also found NA significantly inhibited the migration of b16-f10 cells, but did not affect its survival. These results suggest that NA treatment may be developed into a potential therapy for melanoma.

Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology.

Uveal melanoma (UM) is the most common primary intraocular cancer and has a high incidence of metastasis, which lacks any effective treatment. Here, we present zebrafish models of UM, which are driven by melanocyte-specific expression of activating GNAQ or GNA11 alleles, GNAQ/11Q209L , the predominant initiating mutations for human UM. When combined with mutant tp53, GNAQ/11Q209L transgenics develop various melanocytic tumors, including UM, with near complete penetrance. These tumors display nuclear YAP localization and thus phenocopy human UM. We show that GNAQ/11Q209L expression induces profound melanocyte defects independent of tp53 mutation, which are apparent within 3days of development. First, increases in melanocyte number, melanin content, and subcellular melanin distribution result in hyperpigmentation. Additionally, altered melanocyte migration, survival properties, and evasion of normal boundary cues lead to aberrant melanocyte localization and stripe patterning. Collectively, these data show that GNAQ/11Q209L is sufficient to induce numerous protumorigenic changes within melanocytes.

MicroRNA 143-5p regulates alpaca melanocyte migration, proliferation and melanogenesis.

microRNAs (miRNAs) have been shown to be closely involved in the control of melanogenesis and hair colour in mammals. Previous data also indicate that miR-143 regulates cell growth in melanoma. Here, we aimed to investigate the role of miR-143-5p in alpaca melanocytes. We found that miR-143-5p was highly expressed in the cytoplasm of alpaca melanocytes as demonstrated by an in situ hybridization assay. Prediction analysis revealed that miR-143-5p could regulate TGF-β-activated kinase 1 (TAK1) expression, which we confirmed by luciferase reporter assay, indicating that miR-143-5p controls TAK1 expression by directly targeting its 3' untranslated region (UTR). miR-143-5p overexpression decreased TAK1 expression, which led to increased melanocyte migration and proliferation, and downregulation of microphthalmia-associated transcription factor (MITF), which regulates melanin production. These results support a functional role for miR-143-5p in regulating alpaca melanocyte migration, proliferation and melanogenesis through direct targeting of TAK1.

Primary malignant melanoma of the female urethra − a case report

Introduction. Malignant melanoma accounts for 3% of all cancers in Europe. Malignant melanoma of the genitourinary tract is very rare, accounting for 1% of all cases. In addition, primary malignant melanoma of the urethra accounts for 0.2% of all melanomas and 4% of all urethral cancers. The abnormal migration of melanocytes during the embryonic development may explain their occurrence in the urethra. Also, vulva contains a relatively high concentration of melanocytes, so it may be the reason for higher incidence of malignant melanomas in females than in males, especially located at the meatus or in the distal urethra. Case Report. A 60-year-old woman presented with a solid tumor protruding through the vaginal introitus. Computerized tomography revealed a 5 cm large tumor of the urethra, infiltrating the bladder neck and the anterior vaginal wall. In addition, a bilateral pelvic lymphadenopathy was observed. The patient underwent anterior pelvic exenteration with urethrectomy, bilateral pelvic lymphadenectomy and bilateral ureterocutaneostomy, followed by immunochemotherapy. Nonetheless, the patient died 10 months after the surgery. Conclusion. Urethral melanoma is a tumor with a very poor prognosis and high recurrence rate (71%), even after wide surgical resection, adjuvant radiotherapy, chemo and immunotherapy.

Abstract A73: GD3 ganglioside-enriched extracellular vesicles stimulate melanocyte migration

Abstract Gangliosides are sialic acid-containing glycosphingolipids located mainly in outlet membrane plasma. Tumors usually accumulate gangliosides as disialoganglioside GD3 which is widely expressed in melanomas and neuroblastomas. GD3 has been associated with tumor progression, conferring tumorigenic characteristics to cells such as increased proliferation and migration. In order to investigate the role of GD3 in cell migration, we have transfected the GD3 synthase gene (ST8Sia I) in a melanocyte cell line. In this work we have demonstrated that overexpression of GD3 upon transfection of GD3 synthase was associated with an increased migratory response towards laminin-1. GD3 and 9-O-acetyl-GD3 gangliosides, which colocalize with integrins in cell lamellipodia, are positive modulators of integrin function in the migratory response while GD3 was left behind as a molecular footprint. Indeed, addition of exogenous GD3 to the cells stimulated cell migration whereas exogenously added GM3 inhibited it. However, depletion of gangliosides using a glucosylceramide synthase inhibitor led cells more migratory. Glycosphingolipids content modulates FGF-2-induced cell migration as we demonstrated that FGF-2 induces cell migration. However, this effect was abolished after using glucosylceramide synthase inhibitor, suggesting that GD3 may modulate the motogenic activity of FGF-2. Finally, we showed that GD3 synthase transfected melanocytes release extracellular vesicles (EVs) enriched in GD3. These EVs are responsible for modulating cell migration response due to increase average velocity of GD3 negative cells as we showed in a real-time wound-healing assay. This study shows that EVs from a subset of GD3 positive cells may contribute to the horizontal signaling propagation to a different subset of GD3 negative cells. Thus, data present here led us to an important insight into how EVs carrying GD3 ganglioside could participate in intercellular communication modulating cellular migration. Citation Format: Andreia H. Otake, Ana Paula M. Duarte, Renata de Freitas Saito, Alexandre F. Ramos, Roger Chammas. GD3 ganglioside-enriched extracellular vesicles stimulate melanocyte migration [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A73.

Interleukin-22 participates in the inflammatory process of vitiligo.

Vitiligo is an acquired depigmentary skin inflammatory disorder. The pathogenesis of inflammatory skin disease involves the release of cytokines from keratinocytes, including interleukin (IL)-1β. IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. Among skin cell populations only keratinocytes are the major targets of IL-22. In the present study, we demonstrated that IL-22 promoting IL-1β secretion from keratinocytes via the Reactive oxygen species (ROS)-NOD-like receptor family, pyrin domain containing 3 (NLRP3)-caspase-1 pathway. It inhibited the expression of protease-activated receptor-2 (PAR-2) of keratinocytes. However, IL-22 had no direct effect on normal human foreskin-derived epidermal melanocytes (NHEM). Considering the closely connection between keratinocytes and melanocytes, and the ability of keratinocytes to produce a plethora of cytokines, in the present work, we examined whether IL-22 could regulate melanocytes functions by keratinocytes participation. Keratinocytes were exposed to IL-22 and the conditional medium was collected. The effect of conditional medium on melanocytes was studied. The expressions of relative proteins were assessed by western blot. Influence of conditional medium on NHEM migration was assessed by Transwell method and the apoptosis by flow cytometry analysis. The IL-22-treating keratinocytes conditional medium inhibited melanogenesis and restrained the expressions of Rab GTPases of NHEM. In addition, the conditional medium suppressed melanocytes migration and induced apoptosis. Our results collectively indicated that IL-22 may potentiate IL-1β-mediated skin inflammation and result in participating in the inflammatory pathogenesis of vitiligo.

There's no place like home - HGF-c-MET signaling and melanocyte migration into the mammalian cochlea

ABSTRACTDuring vertebrate embryonic development, neural crest cells arise from the border region between neural and non-neural ectoderm, migrate to various locations of the embryonic body and differentiate into diverse tissues. In the cochlea of the inner ear, the neural crest cell-derived melanocyte is an important component to form the stria vascularis, a non-sensory structure crucial for auditory function. Our recent conditional knockout study in the mouse indicates that in the absence of HGF-c-MET signaling, neural crest cells properly migrate and find the right region of the prospective stria vascularis in the cochlear epithelium, but fail to start incorporating into the epithelium. Our study has shed light on a homing issue of migrating cells that is evident during development, or in cancer cell metastasis.

KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling.

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF- or NRAS-activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation. Cancer Res; 77(21); 5820-30. ©2017 AACR.

622 The novel factor Active Breakpoint Cluster Region-Related Protein (ABR) contributes to melanocyte migration

It has been reported that skin pigmentation is caused by overproduction of melanin as a result of melanocyte activation. Besides, melanin distribution is known to important factor for forming skin pigmentation. Vertical distribution of melanin is regulated by controlling epidermal turnover. On the other hand, controlling mechanisms of horizontal melanin distribution still remain unclear. In the process of wound closure, melanocyte is known to have an ability to migrate into wound site from marginal region, especially from hair bulge. However, in normal skin condition, melanocyte seems to be retaining on basement membrane despite that melanocytes are densified in pigmented sites according to clinical findings. Therefore, we hypothesized that overcrowding of melanocytes would be involved in skin pigmentation. The purpose of this study is to clarify the factors influencing the mechanism of skin pigmentation focusing on melanocyte distribution. We confirmed that the overcrowding condition during culturing melanocytes increases melanin production per cell. Since melanocytes differentiate directly from neural crest cells same as neural cells, we focused on Active Breakpoint Cluster Region-Related Protein (ABR) which is known to be a factor involved in cellular dynamics of neurons. As a result of analyzing the gene function, ABR knocked-down melanocyte enhanced cell migration and decrease melanocytes densities. Furthermore, ABR knocked-down melanocyte decreased melanin production. From the results of the microarray, ABR was confirmed to be involved in the expression of Rho family such as Rac1. These results indicated the possibility of ABR controlling cellular dynamics especially cell polarity and cytoskeletal remodeling. It was suggested that ABR induces melanocyte congestion by suppressing cell polarity regulatory factors and ABR could be novel factor controlling skin pigmentation.

Clinicopathologic features and pathogenesis of melanocytic colonization in atypical meningioma

Only two prior cases of benign dendritic melanocytes colonizing a meningioma have been reported. We add a third case, describe clinicopathologic features shared by the three, and elucidate the risk factors for this very rare phenomenon. A 29 year-old Hispanic woman presented with headache and hydrocephalus. MRI showed a lobulated enhancing pineal region mass measuring 41 mm in greatest dimension. Subtotal resection of the mass demonstrated an atypical meningioma, WHO grade II, and the patient subsequently underwent radiotherapy. She presented 4 years later with diplopia, and MRI showed an enhancing extra-axial mass measuring 47 mm in greatest dimension and centered on the tentorial incisura. Subtotal resection showed a brain-invasive atypical meningioma with melanocytic colonization. The previous two cases in the literature were atypical meningiomas, one of which was also brain invasive. Atypical meningiomas may be at particular risk for melanocytic colonization as they upregulate molecules known to be chemoattractants for melanocytes. We detected c-Kit expression in a minority of the melanocytes as well as stem cell factor and basic fibroblast growth factor in the meningioma cells, suggesting that mechanisms implicated in normal melanocyte migration may be involved. In some cases, brain invasion with disruption of the leptomeningeal barrier may also facilitate migration from the subarachnoid space into the tumor. Whether there is low-level proliferation of the dendritic melanocytes is unclear. Given that all three patients were non-Caucasian, meningiomas in persons and/or brain regions with increased dendritic melanocytes may predispose to colonization. The age range spanned from 6 years old to 70 years old. All three patients were female. The role of gender and estrogen in the pathogenesis of this entity remains to be clarified. Whether melanocytic colonization may also occur in the more common Grade I meningiomas awaits identification of additional cases.

Giant Congenital Melanocytic Nevus (GCMN) - A New Hope for Targeted Therapy?

We present a 6-month-old male patient, who was consulted with dermatologist by his parents, because of a pigmented lesion, present since birth, covering almost the all skin of the back and buttocks. A sharply bordered, unequally coloured congenital pigmented nevus, measuring approximately 21 cm in diameter was observed in the whole body skin examination. The lesion was affecting the lower 2/3 of the skin of the back and the top half of the gluteus area, extending to the lateral part of the tors, forward the abdomen and the upper lateral part of the hips, composed by multiple darker-pigmented nests and several lighter areas, with single depigmented zones, hairy surface, irregularly infiltrated on palpation. Congenital melanocytic nevi are presented in approximately 1% of newborns, while giant congenital melanocytic nevi (GCMN) are the most uncommon subtype of them; with occurrence rate 1 in 50,000 births. They affect 2% of a total body surface or presenting in a diameter larger than 20 cm in older children. Although not common, the possible malignant transformation remains one of the most important considerations related to them, as the related lifetime risk of melanoma is 4% to 10%. Treatment recommendations include non-surgical methods as dermabrasion only within the first two weeks of life, for prevention the possible melanocytic deeper migration, while serial surgical excisions or tissue expanders could be useful treatment tool even in later stages. Nevertheless, cosmetic result is not always satisfactory, and the risk of malignant changes remains, in cases of previous melanocytic migration in deeper layer. Recent article suggests the potential role in the treatment of GCMN with NRAS inhibitor trametinib, approved for treatment of advanced melanoma, associated with underlying NRAS mutations. Although promising, the drug could be useful in paediatric patients, only with associated NRAS gene mutation. It is still unclear whether it could be helpful, independent of the NRAS status.

Improvement of Hair Graying during a Treatment of Male Pattern Hair Loss Using 1,927-nm Fractionated Thulium Laser Energy and Polydeoxyribonucleotide Injections

Hair graying is a common age-related hair change with tremendous social and cosmetic concerns among aged individuals. Many mechanisms contribute to hair graying, such as defective melanocyte stem cell renewal, melanocyte apoptosis, and melanocyte migration defects. Accumulation of oxidative stress has been regarded as a key factor influencing these processes. However, currently, there is no standard treatment for reversing hair graying. Herein, we report our observation of improvement of hair graying in a patient with male pattern hair loss during combined treatment with 1,927-nm fractionated thulium laser energy and intra-perifollicular polydeoxyribonucleotide injections. The patient showed increased numbers of pigmented hair follicles and clinical improvement in hair graying after 12 sessions of combined treatment. Accordingly, we suggest that the combined treatment described in this report may be a promising therapeutic method for treating hair graying.

Unilateral Idiopathic Sensory Trigeminal Nerve Paralysis in a Dog

Background: A spayed-female mixed breed dog was presented due to 2 years reduced visual acuity in the left eye. The investigation revealed corneal melanosis, keratoconjunctivis sicca and loss of facial sensation in the same side. The aim of this report is to describe an unilateral idiopathic sensory trigeminal nerve paralysis and keratitis as consequence of corneal innervation loss was established. Unilateral sensory trigeminal nerve paralysis is a very rare lesion in dogs and causes are unclear.Case: A 5-year-old spayed-female mixed breed dog was presented with a history of two years reduced visual acuity in the left eye. The Schirmer tear test values (without use of topical anesthetic) were 11 and 17 mm/min in the left and right eye respectively. Fluorescein tests were negative for both eyes. All postural reactions and spinal reflexes were normal. Cranial nerve evaluation identified symmetrical facial muscles (temporalis, masseter), indicating no muscle atrophy and normal motor nucleus of the fifth nerve. Absent sensation at the upper and lower lips margins, cornea, eyelids (medial and lateral canthi) and sensation in left nasal side were noted. No palpebral reflex was noticed, but there was spontaneous blinking of eyelids, which indicated normal facial nerve function. All other cranial nerve reflexes including menace response, oculocephalic, and gag reflexes were normal. The owner declined further workup, including cerebrospinal fluid analysis and images studies. According to the clinical presentation and neurological findings, presumptive diagnosis of unilateral idiopathic sensory trigeminal nerve paralysis was established. The dog was observed over 18 months without any clinical improvement. The Schirmer tear test showed same values (12 mm/min) and the melanosis remained unchanged.Discussion: Lesions that affected trigeminal nerve, trigeminal ganglion, or trigeminal tract in the pons and medulla caused facial hypoalgesia or analgesia. The causes of trigeminal nerve damage included neoplasia, trauma, fracture of petrous temporal bone and inflammatory polyneuropathies, but the dog present no signals of these diseases. Trigeminal nerve lesions that affected ophthalmic nerve branch will result in loss of corneal sensation and loss of corneal and palpebral reflex as consequence. Paralysis of this branch cause degenerative changes in the cornea, as neurotrophic keratitis that result in edema and epitelial erosion. The Schirmer tear is the standard test to quantify aqueous tear production and the result (11 mm/min) in dog’s left eye is considered early or subclinical keratoconjunctivis sicca (KCS) sign. The pigmentation results from melanocytic cells migration from the limbal or perilimbal tissues. The keratitis can be active when followed by corneal vascularization, stromal inflammatory cell infiltration and granulation tissue formation. The etiology for idiopathic disease is unknown and isolated sensory trigeminal neuropathy have never been described in dogs. There is no definitive treatment and corticosteroid therapy did not appear to alter the course of the disease in dogs with idiopathic trigeminal neuritis therefore supportive treatment is indicated. The paralysis of trigeminal sensory ophthalmic and maxillary branches can result in corneal alterations.

Lymph nodes' capsular naevi are associated with high naevus count in melanoma patients: a case-control study.

Capsular naevi (CNs) in lymph nodes (LNs) are relatively common, occurring in 3-22% of patients who undergo LN surgery for melanoma. Naevus count is one of the principal risk factors for melanoma, as well as a prognostic factor in melanoma patients. However, little is known about the occurrence of CN in melanoma patients on the basis of their naevus count. A case-control study was performed, to look at the naevus count differences between CN-positive and CN-negative melanoma patients. Cases (CN positive) were matched for age, sex and Breslow thickness with controls (CN negative). Total naevus count was recorded at diagnosis and compared between the two groups. This study was conducted in a tertiary referral academic centre for skin cancer. Twenty-two positive CN patients were matched with 22 negative CN patients. The mean Breslow thickness was 2.66 mm (range: 0.6-9). Positive CN patients were significantly associated with an increasing naevus count on their skin (P=0.02). Patients with more than 100 naevi reported an odds ratio of 7.78 on having a CN compared with patients with fewer than 50 naevi on their skin (P=0.02). An increased melanocytic migration to LNs might be the reason for the association between CNs and a high number of melanocitic naevi on the skin. This could shed some light on the physiology of melanocytes and could be an easy way to predict patients at greater risk of having CNs.

UVB represses melanocyte cell migration and acts through β-catenin.

The exposure of skin to ultraviolet (UV) radiation can have both beneficial and deleterious effects: it can lead, for instance, to increased pigmentation and vitamin D synthesis but also to inflammation and skin cancer. UVB may induce genetic and epigenetic alterations and have reversible effects associated with post-translational and gene regulation modifications. β-catenin is a main driver in melanocyte development; although infrequently mutated in melanoma, its cellular localization and activity are frequently altered. Here, we evaluate the consequence of UVB on β-catenin in the melanocyte lineage. We report that in vivo, UVB induces cytoplasmic/nuclear relocalization of β-catenin in melanocytes of newborn mice and adult human skin. In mouse melanocyte and human melanoma cell lines in vitro, UVB increases β-catenin stability, accumulation in the nucleus and cotranscriptional activity, leading to the repression of cell motility and velocity. The activation of the β-catenin signalling pathway and its effect on migration by UVB are increased by an inhibitor of GSK3β, and decreased by an inhibitor of β-catenin. In conclusion, UVB represses melanocyte migration and does so by acting through the GSK3-β-catenin axis.

P53 regulates ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation

We previously reported that three point mutations in SASH1 and mutated SASH1 promote melanocyte migration in dyschromatosis universalis hereditaria (DUH) and a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. However, the underlying mechanism of molecular regulation to cause this hyperpigmentation disorder still remains unclear. In this study, we aimed to investigate the molecular mechanism undergirding hyperpigmentation in the dyschromatosis disorder. Our results revealed that SASH1 binds with MAP2K2 and is induced by p53‐POMC‐MC1R signal cascade to enhance the phosphorylation level of ERK1/2 and CREB. Moreover, increase in phosphorylated ERK1/2 and CREB levels and melanogenesis‐specific molecules is induced by mutated SASH1 alleles. Together, our results suggest that a novel SASH1/MAP2K2 crosstalk connects ERK1/2/CREB cascade with p53‐POMC‐MC1R cascade to cause hyperpigmentation phenotype of DUH.

Vitiligo Pathogenesis and Emerging Treatments.

The pathogenesis of vitiligo involves interplay between intrinsic and extrinsic melanocyte defects, innate immune inflammation, and T-cell-mediated melanocyte destruction. The goal of treatment is to not only halt disease progression but also promote repigmentation through melanocyte regeneration, proliferation, and migration. Treatment strategies that address all aspects of disease pathogenesis and repigmentation are likely to have greatest efficacy, a strategy that may require combination therapies. Current treatments generally involve nontargeted suppression of autoimmunity, whereas emerging treatments are likely to use a more targeted approach based on in-depth understanding of disease pathogenesis, which may provide higher efficacy with a good safety profile.

Adipocyte Secretome Increases Radioresistance of Malignant Melanocytes by Improving Cell Survival and Decreasing Oxidative Status.

Radiotherapy is a treatment option for the majority of malignancies. However, because melanoma is known to be radioresistant, the use of ionizing radiation as an adjuvant therapy in cutaneous melanoma patients is ineffective. Obesity has now been recognized as a risk factor for melanoma. High adiposity is generally associated with a more pro-oxidative status. Oxidative stress is a major player in radiation therapy and also a common link between obesity and cancer. Several adipocyte-released proteins are known to have a role in controlling cellular growth and pro-survival signaling. For that reason, we investigated the influence of 3T3-L1 mature adipocyte secretome in B16-F10 malignant melanocyte radiosensitivity. We evaluated B16-F10 cell survival and redox homeostasis when exposed to four daily doses of ionizing radiation (2 Gy per day) up to a total of 8 Gy in a medical linear accelerator. B16-F10 melanocytes exhibited slight alterations in survival, catalase activity, nitrative stress and total oxidant concentration after the first 2 Gy irradiation. The motility of the melanocytes was also delayed by ionizing radiation. Subsequent irradiations of the malignant melanocytes led to more prominent reductions in overall survival. Remarkably, 3T3-L1 adipocyte-secreted molecules were able to increase the viability and migration of melanocytes, as well as lessen the pro-oxidant burden induced by both the single and cumulative X-ray doses. In vitro adipocyte-released factors protected B16-F10 malignant melanocytes from both oxidative stress and loss of viability triggered by radiation, enhancing the radioresistant phenotype of these cells with a concomitant activation of the AKT signaling pathway. These results both help to elucidate how obesity influences melanoma radioresistance and support the usage of conventional medical linear accelerators as a valid model for the in vitro radiobiological study of tumor cell lines.

Mutations in γ-secretase subunit–encoding PSENEN underlie Dowling-Degos disease associated with acne inversa

Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.

Cellular and ultrastructural characterization of the grey-morph phenotype in southern right whales (Eubalaena australis).

Southern right whales (SRWs, Eubalena australis) are polymorphic for an X-linked pigmentation pattern known as grey morphism. Most SRWs have completely black skin with white patches on their bellies and occasionally on their backs; these patches remain white as the whale ages. Grey morphs (previously referred to as partial albinos) appear mostly white at birth, with a splattering of rounded black marks; but as the whales age, the white skin gradually changes to a brownish grey color. The cellular and developmental bases of grey morphism are not understood. Here we describe cellular and ultrastructural features of grey-morph skin in relation to that of normal, wild-type skin. Melanocytes were identified histologically and counted, and melanosomes were measured using transmission electron microscopy. Grey-morph skin had fewer melanocytes when compared to wild-type skin, suggesting reduced melanocyte survival, migration, or proliferation in these whales. Grey-morph melanocytes had smaller melanosomes relative to wild-type skin, normal transport of melanosomes to surrounding keratinocytes, and normal localization of melanin granules above the keratinocyte nuclei. These findings indicate that SRW grey-morph pigmentation patterns are caused by reduced numbers of melanocytes in the skin, as well as by reduced amounts of melanin production and/or reduced sizes of mature melanosomes. Grey morphism is distinct from piebaldism and albinism found in other species, which are genetic pigmentation conditions resulting from the local absence of melanocytes, or the inability to synthesize melanin, respectively.