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Surgical resection, the mainstay for melanoma treatment, faces challenges due to high tumor recurrence rates and complex postoperative wound healing. Chronic inflammation from residual disease and the risk of secondary infections impede healing. We introduce an innovative, injectable hydrogel system that integrates a multifaceted therapeutic approach. The hydrogel, crosslinked by calcium ions with sodium alginate, encapsulates a blood clot rich in dendritic cells (DCs) chemoattractants and melanoma cell-derived nanovesicles (NVs), functioning as a potent immunostimulant. This in situ recruitment strategy overcomes the limitations of subcutaneous tumor vaccine injections and more effectively achieves antitumor immunity. Additionally, the hydrogel incorporates Chlorella extracts, enhancing its antimicrobial properties to prevent wound infections and promote healing. One of the key findings of our research is the dual functionality of Chlorella extracts; they not only expedite the healing process of infected wounds but also increase the hydrogel's ability to stimulate an antitumor immune response. Given the patient-specific nature of the blood clot and NVs, our hydrogel system offers customizable solutions for individual postoperative requirements. This personalized approach is highlighted by our study, which demonstrates the synergistic impact of the composite hydrogel on preventing melanoma recurrence and hastening wound healing, potentially transforming postsurgical melanoma management.
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Células Dendríticas , Hidrogeles , Melanoma , Cicatrización de Heridas , Hidrogeles/química , Animales , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Melanoma/terapia , Melanoma/patología , Cicatrización de Heridas/efectos de los fármacos , Humanos , Recurrencia Local de Neoplasia/prevención & control , Ratones Endogámicos C57BL , Antiinfecciosos/uso terapéutico , Antiinfecciosos/farmacología , Ratones , Línea Celular Tumoral , FemeninoRESUMEN
BACKGROUND: Most primary cutaneous melanomas have pathogenesis driven by ultraviolet exposure and genetic mutations, whereas acral lentiginous melanoma (ALM) and metastatic melanoma are much less, if at all, linked with the former. Thus, we evaluated both ultraviolet related and non-ultraviolet related melanomas. Mutations in the MUC16 and TTN genes commonly occur concurrently in these melanoma patients, but their combined prognostic significance stratified by gender and cancer subtype remains unclear. METHODS: The cBioPortal database was queried for melanoma studies and returned 16 independent studies. Data from 2447 melanoma patients were utilized including those with ALM, cutaneous melanoma (CM), and melanoma of unknown primary (MUP). Patients were grouped based on the presence or absence of MUC16 and TTN mutations. Univariate Cox regression and Student's t-tests were used to analyze hazard ratios and total mutation count comparisons, respectively. RESULTS: TTN mutations, either alone or concurrently with MUC16 mutations, significantly correlated with worse prognosis overall, in both genders, and in CM patients. ALM patients with both mutations had better prognoses than CM patients, while ALM patients with neither mutation had worse prognosis than CM patients. For MUP patients, only MUC16 mutations correlated with worse prognosis. ALM patients with neither MUC16 nor TTN mutations had significantly more total mutations than MUP patients, followed by CM patients. CONCLUSION: TTN mutations are a potential marker of poor prognosis in melanoma, which is amplified in the presence of concurrent MUC16 mutations. ALM patients with neither gene mutations had worse prognosis, suggesting a protective effect of having both MUC16 and TTN mutations. Only MUC16 mutations conferred a worse prognosis for MUP patients. Comprehensive genetic profiling in melanoma patients may facilitate personalized treatment strategies to optimize patient outcomes.
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Conectina , Melanoma , Mutación , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/mortalidad , Melanoma/patología , Femenino , Masculino , Pronóstico , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Conectina/genética , Antígeno Ca-125 , Factores Sexuales , Proteínas de la Membrana/genética , Anciano , Biomarcadores de Tumor/genética , AdultoRESUMEN
BACKGROUND: Precancerous and malignant tumours arise within the oral cavity from a predisposed "field" of epithelial cells upon exposure to carcinogenic stimulus. This phenomenon is known as "Field Cancerization". The molecular genomic and transcriptomic alterations that lead to field cancerization and tumour progression is unknown in Indian Oral squamous cell carcinoma (OSCC) patients. METHODS: We have performed whole exome sequencing, copy-number variation array and whole transcriptome sequencing from five tumours and dysplastic lesions (sampled from distinct anatomical subsites - one each from buccal anterior and posterior alveolus, dorsum of tongue-mucosal melanoma, lip and left buccal mucosa) and blood from a rare OSCC patient with field cancerization. RESULTS: A missense CASP8 gene mutation (p.S375F) was observed to be the initiating event in oral tumour field development. APOBEC mutation signatures, arm-level copy number alterations, depletion of CD8 + T cells and activated NK cells and enrichment of pro-inflammatory mast cells were features of early-originating tumours. Pharmacological inhibition of CASP8 protein in a CASP8-wild type OSCC cell line showed enhanced levels of cellular migration and viability. CONCLUSION: CASP8 alterations are the earliest driving events in oral field carcinogenesis, whereas additional somatic mutational, copy number and transcriptomic alterations ultimately lead to OSCC tumour formation and progression.
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Caspasa 8 , Variaciones en el Número de Copia de ADN , Melanoma , Neoplasias de la Boca , Transcriptoma , Humanos , Caspasa 8/genética , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Melanoma/genética , Melanoma/patología , Transcriptoma/genética , Variaciones en el Número de Copia de ADN/genética , Secuenciación del Exoma , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Masculino , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Mutación Missense/genética , Femenino , Persona de Mediana Edad , Linfocitos T CD8-positivosRESUMEN
Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.
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Quitosano , Dextranos , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Melanoma , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Quitosano/química , Quitosano/análogos & derivados , Dextranos/química , Animales , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/inmunología , Ratones , Humanos , Epigénesis Genética/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Hidrogeles/química , Línea Celular Tumoral , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
BACKGROUND: Cutaneous melanoma (CM) is associated with a higher mortality rate than most other skin cancers. The purpose of this expert consensus panel was to review the published literature on new technological advancements for the diagnosis and prognosis for CM and provide updated guidance on their usage. METHODS: A comprehensive literature search of PubMed, Scopus, and Google Scholar was completed for English-language original research articles on the topics of non-invasive diagnostic and prognostic testing for CM, including gene expression profiling (GEP) and electrical impedance spectroscopy (EIS). A panel of 10 dermatologists with significant expertise in the treatment of CM gathered to review the articles and create consensus statements. A modified Delphi process was used to approve each statement and a strength of recommendation was assigned using widely recognized Strength of Recommendation Taxonomy criteria. RESULTS: The literature search produced 200 articles that met the criteria. A screening of the studies resulted in 19 articles. These were distributed to all panelists for review prior to a roundtable discussion. The panel unanimously voted to adopt 7 consensus statements and recommendations, 5 of which were given a strength of "A", 1 of which was given a strength of "B," and 1 of which was given a strength of "C". CONCLUSION: The 2-GEP test and EIS can aid in the precise diagnosis of clinically indeterminate lesions and the 23-GEP test can be used when histopathology is equivocal. The 31-GEP test can enhance prognostic assessment beyond AJCC8 staging and improve clinical decision-making. J Drugs Dermatol. 2024;23(9):774-781. doi:10.36849/JDD.8365R1.
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Consenso , Espectroscopía Dieléctrica , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Pronóstico , Espectroscopía Dieléctrica/métodos , Perfilación de la Expresión Génica , Técnica DelphiRESUMEN
Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2Y641F interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by Ezh2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models, we further investigated the role of pathways downstream of Ezh2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of a wild-type or Ezh2Y641F epigenetic state. We found that the Atg7 locus is controlled by multiple Ezh2 and Stat3 binding sites, Atg7 expression is dependent on Stat3 expression, and that deletion of Atg7 slows down melanoma cell growth in vivo, but not in vitro. Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.
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Proteína 7 Relacionada con la Autofagia , Proteína Potenciadora del Homólogo Zeste 2 , Factor de Transcripción STAT3 , Animales , Factor de Transcripción STAT3/metabolismo , Ratones , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BL , Regulación Neoplásica de la Expresión Génica , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/genética , Melanoma/patología , Epigénesis Genética , Línea Celular Tumoral , Humanos , Autofagia/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismoRESUMEN
The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.
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Melanoma , Invasividad Neoplásica , Staphylococcus aureus , Pez Cebra , Animales , Pez Cebra/microbiología , Melanoma/patología , Melanoma/microbiología , Línea Celular Tumoral , Lípidos/química , Movimiento Celular/efectos de los fármacos , Larva/microbiología , Humanos , Proteínas de Pez Cebra/metabolismo , Agregación Celular/efectos de los fármacosRESUMEN
Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte function, development and plays a significant role in melanoma pathogenesis. MITF genomic amplification promotes melanoma development, and it can facilitate resistance to multiple therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state.
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Regulación Neoplásica de la Expresión Génica , Isocitrato Deshidrogenasa , Melanoma , Factor de Transcripción Asociado a Microftalmía , Especies Reactivas de Oxígeno , Pez Cebra , Factor de Transcripción Asociado a Microftalmía/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Especies Reactivas de Oxígeno/metabolismo , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Animales , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Línea Celular Tumoral , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Daño del ADN , Transcripción GenéticaRESUMEN
Extracellular adenosine is extensively involved in regulating the tumor microenvironment. Given the disappointing results of adenosine-targeted therapy trials, personalized treatment might be necessary, tailored to the microenvironment status of individual patients. Here, we introduce the adenosine signaling score (ADO-score) model using non-negative matrix fraction identified patient subtypes using publicly available melanoma dataset, which aimed to profile adenosine signaling-related genes and construct a model to predict prognosis. We analyzed 580 malignant melanoma samples and demonstrated its robust value for prognosis. Further investigation in immune checkpoint inhibitor dataset suggests its potential as a stratified factor of immune checkpoint inhibitor efficacy. We validated the power of the ADO-score at the protein level immunofluorescence in a melanoma cohort from Xiangya Hospital. More importantly, single-cell and spatial transcriptomic data highlighted the cell-specific expression patterns of adenosine signaling-related genes and the existence of adenosine signaling-mediated crosstalk between tumor cells and immune cells in melanoma. Our study reveals a robust connection between adenosine signaling and clinical benefits in melanoma patients and proposes a universally applicable adenosine signaling model, the ADO-score, in gene expression profiles and histological sections. This model enables us to more precisely and conveniently select patients who are likely to benefit from immunotherapy.
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Adenosina , Inmunoterapia , Melanoma , Transducción de Señal , Microambiente Tumoral , Humanos , Melanoma/genética , Melanoma/patología , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Adenosina/metabolismo , Adenosina/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Transducción de Señal/genética , Pronóstico , Regulación Neoplásica de la Expresión Génica/genética , Transcriptoma/genética , Perfilación de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Masculino , MultiómicaRESUMEN
AIM: To evaluate the role of early prophylactic inguinal node dissection in patients with squamous cell cancer and melanoma of lower limb. MATERIALS AND METHODS: From 2008 to 2018, a Tertiary Care Hospital connected to a teaching institute served as the site of this retrospective observational study. Patient records were gathered with the purpose of gathering clinical, investigative, surgical, pathological and follow-up information. RESULTS: We included 33 patients in this analysis out of the 47 patients we treated ourselves between 2008 and 2018; among these 33 patients, 21 (63.63%) had palpable inguinal nodes at the time of primary presentation. All 21 patients' FNAC tests were positive for metastases, in 16 patients (76.19%). 5 patients on FNAC (23.80%) exhibited not metastases. The remaining 12 patients did not have enlarged lymph nodes at the time of their initial presentation. Patients who did not have palpable lymph node were given the option of having a modified inguinal block dissection. 8 patients with metastatic disease have nodes that are positive in histology. In addition, out of 5 patients with negative nodes 4 (80%) showed evidence of metastasis. CONCLUSION: The conclusion of this retrospective observational study is that although palpable lymph nodes in groin are unquestionably a sign that inguinal nodes should be dissected, prophylactic lymph node dissection should be still done even if nodes are not palpable or provide a negative FNAC result. Given that delayed lymphadenectomy has a significant effect on survival, delaying inguinal lymphadenectomy in non-palpable nodes could cause you to lose the battle against cancer in your lower limb. The related surgical morbidity is the only downside to prophylactic lymph node dissection. This can, however, be effectively decreased with a modified inguinal lymphadenectomy operation.
Résumé Objectif:Évaluer le rôle de la dissection prophylactique précoce du ganglion inguinal chez les patients atteints d'un cancer épidermoïde et d'un mélanome du membre inférieur.Matériels et méthodes:De 2008 à 2018, un hôpital de soins tertiaires relié à un institut d'enseignement a servi de site à cette étude observationnelle rétrospective. Les dossiers des patients ont été rassemblés dans le but de recueillir des informations cliniques, d'investigation, chirurgicales, pathologiques et de suivi.Résultats:Nous avons inclus 33 patients dans cette analyse sur les 47 patients que nous avons nous-mêmes traités entre 2008 et 2018; parmi ces 33 patients, 21 (63,63 %) avaient des ganglions inguinaux palpables au moment de la présentation primaire. Les tests FNAC des 21 patients étaient positifs pour les métastases, chez 16 patients (76,19 %). 5 patients sous FNAC (23,80%) ne présentaient pas de métastases. Les 12 patients restants ne présentaient pas d'hypertrophie des ganglions lymphatiques au moment de leur présentation initiale. Les patients qui n'avaient pas de ganglion lymphatique palpable ont eu la possibilité de subir une dissection par bloc inguinal modifié. 8 patients atteints d'une maladie métastatique ont des ganglions positifs en histologie. De plus, sur 5 patients présentant des ganglions négatifs, 4 (80 %) présentaient des signes de métastases.Conclusion:La conclusion de cette étude observationnelle rétrospective est que même si les ganglions lymphatiques palpables dans l'aine sont incontestablement un signe que les ganglions inguinaux doivent être disséqués, un curage prophylactique des ganglions lymphatiques doit toujours être effectué même si les ganglions ne sont pas palpables ou fournissent un résultat FNAC négatif. Étant donné que le retardement du curage lymphatique a un effet significatif sur la survie, retarder le curage inguinal des ganglions non palpables pourrait vous faire perdre la bataille contre le cancer du membre inférieur. La morbidité chirurgicale associée est le seul inconvénient du curage prophylactique des ganglions lymphatiques. Ceci peut cependant être efficacement réduit grâce à une opération de lymphadénectomie inguinale modifiée.
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Carcinoma de Células Escamosas , Conducto Inguinal , Extremidad Inferior , Escisión del Ganglio Linfático , Ganglios Linfáticos , Metástasis Linfática , Melanoma , Humanos , Escisión del Ganglio Linfático/métodos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Melanoma/cirugía , Melanoma/patología , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Adulto , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Anciano , Extremidad Inferior/cirugía , Conducto Inguinal/cirugía , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Ingle/cirugíaRESUMEN
Invasive growth is a critical process in tumor progression, requiring the activation of various molecular processes in tumor cells at the invasive front. Intercellular communication between heterogeneous tumor cells enhances cellular activation and adaptation to specific microenvironments. One mechanism of intercellular communication is the delivery of miRNAs through tumor cell-derived extracellular vesicles (EVs). In this context we have observed that conditioned media from a highly invasive cell subpopulation (BLM-HI) enhances the invasive capacity of the parental cell line (BLM). Therefore, we hypothesized that this complex change of cellular behavior is influenced by EV-transported miRNAs. The treatment of BLM cells with EVs derived from BLM-HI cells resulted in a significantly enhanced invasive capacity, as observed in Matrigel-embedded spheroids and in 2D Boyden chamber assays, with a dose-dependent effect. Conversely, the invasive capacity of BLM cells was reduced when secretion of EVs was inhibited by a sphingomyelinase inhibitor. To investigate the molecular mechanisms behind this effect, we performed next-generation sequencing and identified an enrichment of miR-1246 in these EVs. In functional analyses we demonstrated that both the EV mediated delivery of miR-1246 as well as overexpression contributes to the enhanced invasiveness of BLM cells. We identified a binding site of miR-1246 in the 3'UTR of cyclin G2 (CCNG2) and demonstrated direct binding by a luciferase reporter assay.Increased expression of CCNG2 has been associated with cancer metastasis and poor patient outcomes in other malignancies. Our study demonstrates that intercellular communication contributes to the transfer of properties, such as increased invasive capacity, between heterogeneous melanoma cells via EV-transported miRNAs.
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Vesículas Extracelulares , Melanoma , MicroARNs , Invasividad Neoplásica , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genéticaRESUMEN
This study examined the thermal signature of pigmented lesions observed by digital infrared thermal imaging as a possible adjunct to physician diagnosis. Thermal images of pigmented lesions were compared to clinical examination by a plastic surgeon interested in skin diseases, dermatoscopy, and histopathology. A total of 35 patients with 55 pigmented skin lesions were considered. We found that all lesions emitting a dark signal on thermal imaging, compared to the nearby skin, were benign, while only one of all benign lesions (1.9%) had a bright "warm" signal. Benign lesions with papule/nodular morphology were dark in 87.5% of patients. All lesions diagnosed as malignant melanoma, both dermatoscopically and histologically, had plaque morphology; yet, only half demonstrated some signals on thermal imaging. Based on these results, we concluded that thermal imaging could be used as an adjunct to diagnosis when examining skin lesions. This study provided an introduction to using thermal imaging for spotting skin lesions.
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Rayos Infrarrojos , Melanoma , Neoplasias Cutáneas , Termografía , Humanos , Termografía/métodos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/diagnóstico por imagen , Melanoma/patología , Melanoma/diagnóstico , Melanoma/diagnóstico por imagen , Femenino , Masculino , Adulto , Persona de Mediana Edad , Dermoscopía/métodos , Anciano , Adulto Joven , AdolescenteRESUMEN
BACKGROUND: Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. RESULTS: We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared "murine MRD genes" profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. CONCLUSIONS: Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies.
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Modelos Animales de Enfermedad , Melanoma , Neoplasia Residual , Animales , Melanoma/genética , Melanoma/patología , Ratones , Leucemia/genética , Leucemia/patología , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Ratones Endogámicos C57BL , Proteómica , Transcriptoma , Perfilación de la Expresión Génica , MultiómicaRESUMEN
INTRODUCTION: Cutaneous malignant melanomas rarely occur in the eye, usually in the eyelids or the conjunctiva. Conjunctival malignant melanomas are even rarer. Most melanomas are dark in color as they are pigmented. However, amelanotic conjunctival malignant melanomas, a scarce variant of the cancer, can be challenging to diagnose accurately. CASE PRESENTATION: We present two cases of white Caucasian Swedish-born women who were diagnosed with unilateral amelanotic malignant melanoma in the conjunctiva of the eye. In the first case, the patient was an 81-year-old woman who was suffering from redness and foreign body sensation in the left eye. The initial diagnosis was blepharitis. Three biopsies were taken, which showed malignant melanoma in the eyelid and the conjunctiva. Unfortunately, the eye and the rest of the orbit could not be saved, and the patient had to undergo an orbital exenteration. In the second case, the patient was a 50-year-old woman, and the tumor was localized in the temporal conjunctiva of the left eye. The initial diagnosis was pinguecula, but at the time of surgery, the physician suspected conjunctival intraepithelial neoplasia. The tumor was not completely removed, so adjuvant brachytherapy and local chemotherapy were used. The eye was preserved. No neck and/or lung metastasis was detected in either case at the time of diagnosis. CONCLUSIONS: Conjunctival amelanotic malignant melanomas should be suspected when tumors are present in the eye and/or the eyelids. By suspecting amelanotic malignant melanoma, the delay in treatment can be shortened. Treating them as soon as possible is essential to minimize the risk of metastasis.
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Neoplasias de la Conjuntiva , Melanoma Amelanótico , Humanos , Femenino , Neoplasias de la Conjuntiva/patología , Neoplasias de la Conjuntiva/terapia , Neoplasias de la Conjuntiva/diagnóstico , Melanoma Amelanótico/patología , Melanoma Amelanótico/diagnóstico , Anciano de 80 o más Años , Persona de Mediana Edad , Melanoma/patología , Melanoma/diagnósticoRESUMEN
BACKGROUND: Numerous melanoma-specific dermoscopic features have been described in invasive melanomas, while fewer features are found in melanoma in situ (MIS) and atypical nevi (ATN). Consensus regarding which features are critical for the differentiation of MIS from ATN has not been reached. PURPOSE: Determine 1) whether there are dermoscopic features that differentiate early MIS from ATN, and 2) whether non-invasive assessment of genomic biomarkers (LINC00518 and PRAME) can aid in patient management. METHODS: From 2018 to 2023, 56 melanomas were evaluated for 5 clinical and 13 dermoscopic features and melanoma-associated genomic biomarkers. Two groups of ATN with positive and negative genomic biomarkers were randomly selected for comparison. RESULTS: All melanomas in this study expressed one or both melanoma-associated genomic markers. MIS had an average of 3.90 (range, 2-7) of the 13 dermoscopic features, while invasive melanomas had an average of 4.44 (range, 3-6). Sixteen of 40 (40%) MIS and 3 of 16 (18.8%) invasive melanomas had 3 or fewer dermoscopic features. These findings were comparable to those observed in both ATN groups. The most common dermoscopic features were absent or diminished pigment network, regression structures, and granularity. This combination of features was most helpful in identifying lesions for genomic testing. CONCLUSIONS: Clinical and dermoscopic features alone could not differentiate MIS from ATN. Non-invasive genomic testing helped differentiate lower from higher-risk lesions and aid in clinical management decisions. Genomic testing was particularly helpful in patients with large numbers of lesions with several being considered for biopsy based on clinical and dermoscopic examination. J Drugs Dermatol. 2024;23(9):717-723. doi:10.36849/JDD.8454.
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Dermoscopía , Melanoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/diagnóstico , Melanoma/genética , Melanoma/patología , Melanoma/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Diagnóstico Diferencial , Anciano , Adulto , Genómica , Biomarcadores de Tumor/genética , Nevo Pigmentado/genética , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patología , Anciano de 80 o más AñosRESUMEN
Kv1.3 is a multifunctional potassium channel implicated in multiple pathologies, including cancer. However, how it is involved in disease progression is not fully clear. We interrogated the interactome of Kv1.3 in intact cells using BioID proximity labeling, revealing that Kv1.3 interacts with STAT3- and p53-linked pathways. To prove the relevance of Kv1.3 and of its interactome in the context of tumorigenesis, we generated stable melanoma clones, in which ablation of Kv1.3 remodeled gene expression, reduced proliferation and colony formation, yielded fourfold smaller tumors, and decreased metastasis in vivo in comparison to WT cells. Kv1.3 deletion or pharmacological inhibition of mitochondrial Kv1.3 increased mitochondrial Reactive Oxygen Species release, decreased STAT3 phosphorylation, stabilized the p53 tumor suppressor, promoted metabolic switch, and altered the expression of several BioID-identified Kv1.3-networking proteins in tumor tissues. Collectively, our work revealed the tumor-promoting Kv1.3-interactome landscape, thus opening the way to target Kv1.3 not only as an ion-conducting entity but also as a signaling hub.
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Canal de Potasio Kv1.3 , Factor de Transcripción STAT3 , Transducción de Señal , Proteína p53 Supresora de Tumor , Canal de Potasio Kv1.3/metabolismo , Canal de Potasio Kv1.3/genética , Proteína p53 Supresora de Tumor/metabolismo , Factor de Transcripción STAT3/metabolismo , Humanos , Animales , Ratones , Línea Celular Tumoral , Melanoma/metabolismo , Melanoma/patología , Melanoma/genética , Mitocondrias/metabolismo , Proliferación Celular , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Cutaneous melanoma is an aggressive type of skin cancer that is recognized for its high metastatic potential and the challenges it presents in its treatment. There has been increasing interest in plant extracts and their potential applications in melanoma. The present study aimed to investigate the content of individual phenolic compounds in araçá-boi extract, evaluate their antioxidant activity, and explore their effects on cell viability, migration properties, oxidative stress levels, and protein expression in the human metastatic melanoma cell line SK-MEL-28. HPLC-DAD analysis identified 11 phenolic compounds in the araçá-boi extract. Trans-cinnamic acid was the main phenolic compound identified; therefore, it was used alone to verify its contribution to antitumor activities. SK-MEL-28 melanoma cells were treated for 24 h with different concentrations of araçá-boi extract and trans-cinnamic acid (200, 400, 600, 800, and 1600 µg/mL). Both the araçá-boi extract and trans-cinnamic acid reduced cell viability, cell migration, and oxidative stress in melanoma cells. Additionally, they modulate proteins involved in apoptosis and inflammation. These findings suggest the therapeutic potential of araçá-boi extract and its phenolic compounds in the context of melanoma, especially in strategies focused on preventing metastasis. Additional studies, such as the analysis of specific signaling pathways, would be valuable in confirming and expanding these observations.
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Movimiento Celular , Supervivencia Celular , Cinamatos , Melanoma , Fenoles , Extractos Vegetales , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Movimiento Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Supervivencia Celular/efectos de los fármacos , Cinamatos/farmacología , Línea Celular Tumoral , Fenoles/farmacología , Antioxidantes/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
BACKGROUND: Regulatory mechanism of ERK1 and ERK2, their mechanisms of action, and how they impact on development, growth, and homeostasis of different organisms have been given much emphasis for long. ERK1 and 2 though are isoforms of ERK mitogen-activated protein kinase but are coded by two different genes MAPK3 and MAPK1 respectively and show differential expressions and interdependency in different cancer cell lines. Our previous investigations substantially stated the effect of ERK1 and ERK2 on different extracellular molecules like MMPs and integrins, responsible for cell growth and differentiation. Here, we aim to study individual roles of ERK1 and ERK2 and their interdependency in progression and invasiveness in various cancer cell lines. METHODS: Different cancer cell lines namely B16F10 (melanoma), MCF7, and MDAMB231 (breast cancer) for studying this particular question were used. Methodologies like gelatin zymography, immunoprecipitation, Western blotting, cell invasion assay, wound healing assay, siRNA transfection, and double transfection procedures were followed for our study. RESULTS: Our findings suggest compensation for ERK2 deficiency by pERK1, clear ERK2 predominance in MCF7 cell line, ERK1-ERK2 interdependency in MDAMB231 cells with regard to compensating each other, and significant role of both ERK1 and ERK2 in modulation of MMP9. CONCLUSION: If summarized, our results prove the contribution of ERK2 in compensating ERK1 loss and vice versa and an evident role of ERK1 in cancer cell invasiveness.
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Neoplasias de la Mama , Melanoma , Proteína Quinasa 1 Activada por Mitógenos , Proteína Quinasa 3 Activada por Mitógenos , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Melanoma/patología , Melanoma/genética , Melanoma/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Animales , Ratones , Células MCF-7 , Movimiento Celular , Invasividad Neoplásica , Proliferación CelularRESUMEN
BACKGROUND: Macrophage-based cell therapies have shown modest success in clinical trials, which can be attributed to their phenotypic plasticity, where transplanted macrophages get reprogrammed towards a pro-tumor phenotype. In most tumor types, including melanoma, the balance between antitumor M1-like and tumor-promoting M2-like macrophages is critical in defining the local immune response with a higher M1/M2 ratio favoring antitumor immunity. Therefore, designing novel strategies to increase the M1/M2 ratio in the TME has high clinical significance and benefits macrophage-based cell therapies. METHODS: In this study, we reprogrammed antitumor and proinflammatory macrophages ex-vivo with HDAC6 inhibitors (HDAC6i). We administered the reprogrammed macrophages intratumorally as an adoptive cell therapy (ACT) in the syngeneic SM1 murine melanoma model and patient-derived xenograft bearing NSG-SGM3 humanized mouse models. We phenotyped the tumor-infiltrated immune cells by flow cytometry and histological analysis of tumor sections for macrophage markers. We performed bulk RNA-seq profiling of murine bone marrow-derived macrophages treated with vehicle or HDAC6i and single-cell RNA-seq profiling of SM1 tumor-infiltrated immune cells to determine the effect of intratumor macrophage ACT on the tumor microenvironment (TME). We further analyzed the single-cell data to identify key cell-cell interactions and trajectory analysis to determine the fate of tumor-associated macrophages post-ACT. RESULTS: Macrophage ACT resulted in diminished tumor growth in both mouse models. We also demonstrated that HDAC6 inhibition in macrophages suppressed the polarization toward tumor-promoting phenotype by attenuating STAT3-mediated M2 reprogramming. Two weeks post-transplantation, ACT macrophages were viable, and inhibition of HDAC6 rendered intratumor transplanted M1 macrophages resistant to repolarization towards protumor M2 phenotype in-vivo. Further characterization of tumors by flow cytometry, single-cell transcriptomics, and single-cell secretome analyses revealed a significant enrichment of antitumor M1-like macrophages, resulting in increased M1/M2 ratio and infiltration of CD8 effector T-cells. Computational analysis of single-cell RNA-seq data for cell-cell interactions and trajectory analyses indicated activation of monocytes and T-cells in the TME. CONCLUSIONS: In summary, for the first time, we demonstrated the potential of reprogramming macrophages ex-vivo with HDAC6 inhibitors as a viable macrophage cell therapy to treat solid tumors.
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Macrófagos , Melanoma , Animales , Ratones , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Melanoma/inmunología , Melanoma/patología , Melanoma/terapia , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Línea Celular Tumoral , Microambiente Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Reprogramación Celular , Modelos Animales de EnfermedadRESUMEN
Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease's progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF- metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF-, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients.