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Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identified markers for stem cell populations that maintain distinct regions of the gland and uncovered Hh signaling as a key regulator of stem cell proliferation. Consistent with this, human Meibomian gland carcinoma exhibited increased Hh signaling. Aged glands displayed decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.
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Biomarcadores , Lentigo , MicroRNAs , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lentigo/genética , MicroRNAs/genéticaRESUMO
Chromatin organization is essential for maintaining cell-fate trajectories and developmental programs. Here, we find that disruption of H3K36 methylation dramatically impairs normal epithelial differentiation and development, which promotes increased cellular plasticity and enrichment of alternative cell fates. Specifically, we observe a striking increase in the aberrant generation of excessive epithelial glandular tissues, including hypertrophic salivary, sebaceous, and meibomian glands, as well as enhanced squamous tumorigenesis. These phenotypic and gene expression manifestations are associated with loss of H3K36me2 and rewiring of repressive H3K27me3, changes we also observe in human patients with glandular hyperplasia. Collectively, these results have identified a critical role for H3K36 methylation in both in vivo epithelial cell-fate decisions and the prevention of squamous carcinogenesis and suggest that H3K36 methylation modulation may offer new avenues for the treatment of numerous common disorders driven by altered glandular function, which collectively affect large segments of the human population.
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Carcinoma de Células Escamosas , Histonas , Humanos , Histonas/metabolismo , Plasticidade Celular , Metilação , Carcinogênese/genética , Carcinoma de Células Escamosas/genéticaRESUMO
Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1), controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in the surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Slug, and consequently decreases expression of the Dsg1 transcriptional activator Grhl1. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.
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Desmogleína 1 , Queratinócitos , Melanoma , Humanos , Movimento Celular , Desmogleína 1/genética , Epiderme , Melanoma/genética , Melanoma/patologia , Microambiente Tumoral/genéticaRESUMO
N6-methyladenosine (m6A) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of m6A in a self-renewing somatic tissue, we deleted Mettl3 in epidermal progenitors in vivo. Mice lacking Mettl3 demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that Mettl3 promotes the m6A-mediated degradation of mRNAs encoding critical histone modifying enzymes. Depletion of Mettl3 results in the loss of m6A on these mRNAs and increases their expression and associated modifications, resulting in widespread gene expression abnormalities that mirror the gross phenotypic abnormalities. Collectively, these results have identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for m6A in the regulation of chromatin modifiers, and underscoring a critical role for Mettl3-catalyzed m6A in proper epithelial development and self-renewal.
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Histonas , Metiltransferases , Animais , Camundongos , Metiltransferases/genética , Adenosina , Adesão Celular , RNA Mensageiro , CatáliseRESUMO
BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia seen primarily in women of African descent but rarely reported in men. The etiology of CCCA is unknown, but genetic variants, type 2 diabetes mellitus, and bacterial infections may play a role. OBJECTIVES: We aimed to characterize the demographics, medical histories, and clinical findings of male patients with CCCA with the hypothesis that features may differ from women. METHODS: This was a case series of adult male patients with biopsy-confirmed CCCA seen at an academic dermatology department between 2012 and 2022. RESULTS: In total, 17 males had a scalp biopsy and clinical findings consistent with CCCA. The average age was 43 years, and 88.2% of cases identified as Black race. Scalp pruritus was the most common symptom, and few patients endorsed high-risk hair care practices. None of the cases had diagnosis of type 2 diabetes mellitus, but 17.6% had history of latent tuberculosis, and 47.1% had a positive family history of alopecia. We observed 8 patients with atypical CCCA, and 29.4% had an overlapping scalp diagnosis. LIMITATIONS: This study is limited by the single center, retrospective design and small sample size. CONCLUSIONS: It is important to consider CCCA in the differential diagnosis of alopecia in adult Black males.
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Dermatite , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Estudos Retrospectivos , Negro ou Afro-Americano , Alopecia/etiologia , Alopecia/genética , Couro Cabeludo/patologia , Dermatite/patologia , Cicatriz/complicaçõesRESUMO
GPER (G protein-coupled estrogen receptor) has been reported to play roles in several areas of physiology including cancer, metabolic disorders, and cardiovascular disease. However, the understanding of where this receptor is expressed in human tissue is limited due to limited available tools and methodologies that can reliably detect GPER protein. Recently, a highly specific monoclonal antibody against GPER (20H15L21) was developed and is suitable for immunohistochemistry. Using this antibody, we show that GPER protein expression varies markedly between normal human tissue, and also among cancer tissue. As GPER is an emerging therapeutic target for cancer and other diseases, this new understanding of GPER distribution will likely be helpful in design and interpretation of ongoing and future GPER research.
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Squamous carcinogenesis is incompletely understood, but more recent genetic studies support that the order of acquired mutations is important. This paper will review more recent genetic studies with an emphasis on the potential truncal mutations, mutations critical to the trunk of the cancer evolutionary tree, in actinic keratosis, squamous cell carcinoma in situ, cutaneous squamous cell carcinoma, keratoacanthoma, and keratoacanthoma-like squamous proliferation.
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Dermatite , Líquen Plano , Humanos , Alopecia/etiologia , Linfócitos , Fator de Transcrição STAT3RESUMO
BackgroundAcute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.MethodsA 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient's skin and neutrophils were performed.ResultsWe identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1ß and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.ConclusionDysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding SourcesBerstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.
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Síndrome de Sweet , Feminino , Humanos , Pessoa de Meia-Idade , Síndrome de Sweet/tratamento farmacológico , Síndrome de Sweet/genética , Neutrófilos/patologia , Fosfatidilinositol 3-Quinases/genética , Corticosteroides , Mutação , Classe Ia de Fosfatidilinositol 3-QuinaseRESUMO
ABSTRACT: Cutaneous ganglioneuromas (GNs) are exceptionally uncommon tumors, and many reported cases describe association with overlying epidermal hyperplasia that may be interpreted as seborrheic keratosis (SK) or SK-like proliferation. We report 5 cases of cutaneous GN in adult patients; all of which were discovered incidentally in the immediate vicinity of epidermal hyperplasia. A review of the literature demonstrates the current-although likely imperfect-understanding of the etiopathogenesis of both SK and GN in the skin. We explore the putative pathophysiologies of other common, well-characterized skin lesions and, taking them into account, provide rationale for the coexistence of cutaneous GN with overlying SK and SK-like epidermal changes. However, we ultimately acknowledge a dilemma of causality and, given the rarity of their co-occurrence, objectively question whether occasional cameo appearances by GN lying subjacent to SK and SK-like hyperplasia may be due merely to chance.
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Ganglioneuroma , Ceratose Seborreica , Dermatopatias , Neoplasias Cutâneas , Adulto , Ganglioneuroma/complicações , Humanos , Hiperplasia , Ceratose Seborreica/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologiaRESUMO
Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies.
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Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Humanos , Incidência , Neoplasias Cutâneas/patologia , Estados UnidosRESUMO
Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.
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Dermatite Atópica , Animais , Inteligência Artificial , Dermatite Atópica/patologia , Fibroblastos/patologia , Imunidade , Camundongos , NF-kappa B/metabolismo , Pele/patologiaRESUMO
Low-grade fibromyxoid sarcoma (LGFMS) is a histopathologically deceptive soft tissue neoplasm with bland cytology, which is typically encountered in deep soft tissue of adults. We report two cases of superficial LGFMS in young patients (16 and 21 years old, respectively), which were difficult to diagnose on histopathologic and clinical findings alone. LGFMS commonly mimics benign neoplasms such as cellular neurothekeoma, fibromatosis, neurofibroma, and perineurioma. Malignancies included in the differential diagnosis are soft tissue neoplasms such as dermatofibrosarcoma protuberans and myxofibrosarcoma. A high degree of reported variation in pattern and cellularity among LGFMS further complicates the diagnosis. Careful examination and appropriate immunohistochemistry panels including MUC4 are essential for narrowing the differential diagnosis. Molecular studies for possible FUS translocation can confirm the diagnosis of LGFMS. Sufficient sampling and workup of these lesions are critical, especially in younger patients. Young age and superficial presentation can easily sway dermatopathologists/dermatologists toward an incorrect diagnosis of benignancy.
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Fibroma , Fibrossarcoma , Neoplasias de Bainha Neural , Neoplasias de Tecidos Moles , Adolescente , Adulto , Fibroma/diagnóstico , Fibroma/patologia , Fibrossarcoma/diagnóstico , Fibrossarcoma/patologia , Humanos , Imuno-Histoquímica , Neoplasias de Tecidos Moles/patologia , Adulto JovemRESUMO
HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and in disease are poorly understood. We find that homozygous epidermal codeletion of Hdac1 and Hdac2 in adult mouse epidermis causes reduced basal cell proliferation, apoptosis, inappropriate differentiation, and eventual loss of Hdac1/2-null keratinocytes. Hdac1/2-deficient epidermis displays elevated acetylated p53 and increased expression of the senescence gene p16. Loss of p53 partially restores basal proliferation, whereas p16 deletion promotes long-term survival of Hdac1/2-null keratinocytes. In activated GLI2-driven pre-basal cell carcinoma, Hdac1/2 deletion dramatically reduces proliferation and increases apoptosis, and knockout of either p53 or p16 partially rescues both proliferation and basal cell viability. Topical application of the HDAC inhibitor romidepsin to the normal epidermis or to GLI2ΔN-driven lesions produces similar defects to those caused by genetic Hdac1/2 deletion, and these are partially rescued by loss of p16. These data reveal essential roles for HDAC1/2 in maintaining proliferation and survival of adult epidermal and basal cell carcinoma progenitors and suggest that the efficacy of therapeutic HDAC1/2 inhibition will depend in part on the mutational status of p53 and p16.
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Carcinoma Basocelular/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Epiderme/fisiologia , Queratinócitos/fisiologia , Neoplasias Cutâneas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Apoptose , Carcinogênese , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina/genética , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/genética , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Lesões Pré-Cancerosas , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/genéticaAssuntos
Alopecia , Dermatite , Alopecia/etiologia , Alopecia/patologia , Cicatriz/etiologia , Cicatriz/patologia , Dermatite/patologia , Cabelo/patologia , HumanosRESUMO
The epigenetic regulator, MLL4 (KMT2D), has been described as an essential gene in both humans and mice. In addition, it is one of the most commonly mutated genes in all of cancer biology. Here, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression. Mice lacking epidermal Mll4, but not the related enzyme Mll3 (Kmt2c), display features of impaired differentiation and human precancerous neoplasms, all of which progress with age. Mll4 deficiency profoundly alters epidermal gene expression and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Alox12b, and Aloxe3). Beyond revealing a new mechanistic basis for Mll4-mediated tumor suppression, our data uncover a potentially much broader and general role for ferroptosis in the process of differentiation and skin homeostasis.
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AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs. MATERIALS AND METHODS: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition. RESULTS: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism. CONCLUSION: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.