bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–06–06
fifty-six papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study.
  2. How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance.
  3. Histone Deacetylase inhibitor Vorinostat (SAHA) suppresses micropthalmia transcription factor expression and induces cell death in nevocytes from large/giant congenital melanocytic nevi.
  4. mGPDH Deficiency leads to melanoma metastasis via induced NRF2.
  5. Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients.
  6. Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations.
  7. The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma.
  8. Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line.
  9. Melanoma Cell State-Specific Responses to TNFα.
  10. Identification of Potential Genes Associated with Vemurafenib Efficacy and Melanoma Prognosis.
  11. Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study.
  12. Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.
  13. The role of FoxP3+ regulatory T cells and IDO+ immune and tumor cells in malignant melanoma - an immunohistochemical study.
  14. Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications.
  15. BRAF/EZH2 Signaling Represses miR-129-5p Inhibition of SOX4 Thereby Modulating BRAFi Resistance in Melanoma.
  16. USP8 is a Novel Therapeutic Target in Melanoma Through Regulating Receptor Tyrosine Kinase Levels.
  17. Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model.
  18. Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism.
  19. Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells.
  20. Identification and validation of immune-related lncRNA prognostic signatures for melanoma.
  21. Learning from Embryogenesis-A Comparative Expression Analysis in Melanoblast Differentiation and Tumorigenesis Reveals miRNAs Driving Melanoma Development.
  22. [Molecular background of BRAF inhibitor induced resistance in BRAFV600E mutant melanoma cell lines].
  23. From Melanocytes to Melanoma Cells: Characterization of the Malignant Transformation by Four Distinctly Different Melanin Fluorescence Spectra (Review).
  24. LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells.
  25. Xenopus, an emerging model for studying pathologies of the neural crest.
  26. The pleiotropic role of circular and long non-coding RNAs in cutaneous melanoma.
  27. Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape.
  28. Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?
  29. Neuroendocrine Factors in Melanoma Pathogenesis.
  30. A Small Molecule Antagonist of PD-1/PD-L1 Interactions Acts as an Immune Checkpoint Inhibitor for NSCLC and Melanoma Immunotherapy.
  31. CDK4/6 Inhibitors in Melanoma: A Comprehensive Review.
  32. Mitochondrial DNA polymorphisms and biogenesis genes in primary and metastatic uveal melanoma cell lines.
  33. Evaluation of a Three-Marker Panel for the Detection of Uveal Melanoma Metastases: A Single-Center Retrospective Analysis.
  34. Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas.
  35. CD63 expression in metastatic melanoma and melanocytic nevi in lymph nodes.
  36. Visible light and human skin pigmentation: The importance of skin phototype.
  37. Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants.
  38. Plasma circulating cell free messenger RNA as a potential biomarker of melanoma.
  39. Recognition, Staging, and Management of Melanoma.
  40. PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation.
  41. The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma.
  42. Anti-proliferative and pro-apoptotic activity of glycosidic derivatives of lawsone in melanoma cancer cell.
  43. Early memory differentiation and cell death resistance in T cells predicts melanoma response to sequential anti-CTLA4 and anti-PD1 immunotherapy.
  44. CRISPR/Cas9 uPAR Gene Knockout Results in Tumor Growth Inhibition, EGFR Downregulation and Induction of Stemness Markers in Melanoma and Colon Carcinoma Cell Lines.
  45. Choroidal melanocytes: subpopulations of different origin?
  46. A polymer-lipid membrane artificial cell nanocarrier containing enzyme-oxygen biotherapeutic inhibits the growth of B16F10 melanoma in 3D culture and in a mouse model.
  47. Melanoma pathology: new approaches and classification.
  48. Real-World Experience with Targeted Therapy in BRAF Mutant Advanced Melanoma Patients: Results from a Multicenter Retrospective Observational Study Advanced Melanoma in Russia (Experience) (ADMIRE).
  49. Interpretable deep learning uncovers cellular properties in label-free live cell images that are predictive of highly metastatic melanoma.
  50. Melanoma and eruptive nevi during cetuximab treatment: EGFR inhibitors and a common concern.
  51. Skin Cancer Detection: A Review Using Deep Learning Techniques.
  52. A Novel BLOC1S5-Related HPS-11 Patient and Zebrafish with bloc1s5 Disruption.
  53. Fucosylated Proteome Profiling Identifies a Fucosylated, Non-Ribosomal, Stress-Responsive Species of Ribosomal Protein S3.
  54. Accuracy of clinical-dermatoscopic versus dermatopathologic diagnosis of melanoma and non-melanoma skin cancer.
  55. Afucosylated IgG Targets FcγRIV for Enhanced Tumor Therapy in Mice.
  56. Increased melanoma recurrence in patients with multiple primary invasive melanomas.
  1. J Exp Pharmacol. 2021 ;13 521-535
    Combinatorial Therapies to Overcome BRAF/MEK Inhibitors Resistance in Melanoma Cells: An in vitro Study.
    Helena Pópulo, Beatriz Domingues, Cristina Sampaio, José Manuel Lopes, Paula Soares.
       Background: Melanoma accounts for only 1% of all skin malignant tumors; however, it is the deadliest form of skin cancer. Since 2011, FDA (Food and Drug Administration) approved several novel therapeutic strategies, such as MAPK pathway targeted therapies, to treat cutaneous melanoma patients. However, their improvements in overall survival were limited, due to the development of resistance.
    Methods: In this work, several combinations of therapies, including the metabolic modulator DCA, were tested in melanoma cell lines, considering that MAPK and PI3K/AKT/mTOR pathways are deregulated and interconnected in melanoma and that the presence of the Warburg effect in melanoma cells may influence the response to therapy. The effect of the treatments was assessed in the proliferation and survival of melanoma cell lines with different genetic profiles. Also, the possibility to overcome resistance to the treatment with vemurafenib was tested.
    Results: In general, higher decrease in cell viability and cell proliferation and increase in apoptosis were obtained after the combination treatments, comparing with single treatments, in all the studied cell lines. The combination of cobimetinib and everolimus appear to be the best treatment option. The BRAFV600E -vemurafenib resistant melanoma cell line showed to retain sensitivity to both everolimus and DCA.
    Discussion and Conclusion: Our results suggest that the combination of MAPK pathway inhibitors with mTOR pathway inhibitors and DCA should be considered as therapeutic options to treat melanoma patients, as the combinations potentiated the effects of each drug alone. In a cell line resistant to vemurafenib, we verified that combined MAPK inhibitors with inhibition of mTOR pathway and/or DCA metabolism modulation might constitute possible strategies in order to overcome resistance to MAPK inhibition.
    Keywords:  DCA; cobimetinib; everolimus; melanoma; metabolism; vemurafenib
    DOI:  https://doi.org/10.2147/JEP.S297831
  2. Int J Mol Sci. 2021 May 28. pii: 5761. [Epub ahead of print]22(11):
    How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance.
    Anja Wessely, Theresa Steeb, Carola Berking, Markus Vincent Heppt.
      Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
    Keywords:  FOXD3; MITF; MSX1; PAX3; SOX10; cellular plasticity; melanoma; neural crest; phenotype switch
    DOI:  https://doi.org/10.3390/ijms22115761
  3. Melanoma Res. 2021 May 28.
    Histone Deacetylase inhibitor Vorinostat (SAHA) suppresses micropthalmia transcription factor expression and induces cell death in nevocytes from large/giant congenital melanocytic nevi.
    Dipanjan Basu, Cláudia M Salgado, Bruce Bauer, Ryan M Hoehl, Catherine N Moscinski, Lori Schmitt, Miguel Reyes-Múgica.
      Large/giant congenital nevi (L/GCMN) are benign neoplasms of the melanocytic neural crest lineage covering extensive areas of skin presenting risk for melanoma. Surgical resection often leads to scarring and trauma. Histone deacetylase inhibitors (iHDACs) as topical therapeutic agents may prove beneficial as an alternative/adjunct to surgery in this disease. Here we describe the effect of in vitro treatment of iHDACs drugs on primary nevocytes isolated from L/GCMN patients. Micropthalmia transcription factor (MITF) expression in L/GCMN patients' lesions was detected by immunohistochemistry, in cultured nevocytes by immunofluorescence, immunoblot and quantitative polymerase chain reaction. Cellular senescence was detected by SA-ß galactosidase activity. Markers for melanocytic differentiation were evaluated by immunoblot analysis and extracted melanin content was estimated spectrophotometrically. Cell death was measured by lactate dehydrogenase (LDH) assay and necrosis confirmed by polymerase (PARP) cleavage and acridine orange staining of the nuclei. MITF was expressed ubiquitously in nevocytes and melanocytes in patients' lesions. In culture, iHDAC treatment suppressed MITF protein and mRNA expression resulting in a senescent-like phenotype with positive ß-galactosidase staining, progressing to necrotic cell death as evidenced by increased LDH activity, appearance of cleaved PARP and necrotic nuclei. This is the first report showing evidence of iHDACs-induced MITF suppression in congenital nevocytes in vitro leading to a morphologic change with positive ß-galactosidase staining, followed by necrotic cell death in nevocytes, indicating that iHDAC drugs could be valuable therapeutic agents for treatment of L/GCMN lesions.
    DOI:  https://doi.org/10.1097/CMR.0000000000000749
  4. J Cell Mol Med. 2021 Jun;25(11): 5305-5315
    mGPDH Deficiency leads to melanoma metastasis via induced NRF2.
    Xing Li, Ling Zhou, Yiming Zhang, Xuan He, Hao Lu, Linlin Zhang, Yongfeng Tian, Xiufei Liu, Hongting Zheng, Jiaqing Shao, Min Long.
      Oxidative stress critically influences carcinogenesis and the progression of melanoma, and aggressive malignant melanoma activity is due to its high metastatic ability. Some findings in several cancer cell lines have indicated that mGPDH, a component of the mitochondrial respiratory chain, also modulates oxidative stress. However, the role of mGPDH in melanoma remains elusive. Here, we report that the mGPDH protein level is decreased in human skin melanoma compared to normal skin and decreased in metastatic melanoma compared to primary melanoma. Our in vivo and in vitro experiments indicated that mGPDH depletion accelerated melanoma migration and invasion without affecting proliferation or apoptosis. Mechanistically, we found elevated NRF2 protein levels in human skin melanoma and mGPDH-knockout (ko) metastatic xenografts in the lungs of nude mice. Moreover, in A375 melanoma cells, the loss of mGPDH-induced NRF2 expression but did not affect NRF2 protein degradation. Additionally, melanoma metastasis induced by the loss of mGPDH was rescued by the further down-regulation of NRF2 in vivo and in vitro. Consistently, mGPDH overexpression (oe) depressed NRF2 expression and attenuated the malignant properties of melanoma cells. In conclusion, our findings suggest that mGPDH suppresses melanoma metastasis by inhibiting NRF2 and downstream oxidative signals, highlighting the therapeutic potential of mGPDH for melanoma treatment.
    Keywords:  NRF2; mGPDH; melanoma; metastasis
    DOI:  https://doi.org/10.1111/jcmm.16542
  5. Cancers (Basel). 2021 May 10. pii: 2282. [Epub ahead of print]13(9):
    Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients.
    Sarah Zhou, Daniel Sikorski, Honghao Xu, Andrei Zubarev, May Chergui, François Lagacé, Wilson H Miller, Margaret Redpath, Stephanie Ghazal, Marcus O Butler, Teresa M Petrella, Joël Claveau, Carolyn Nessim, Thomas G Salopek, Robert Gniadecki, Ivan V Litvinov.
      Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III-IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.
    Keywords:  BRAF inhibitor; BRAF mutation; MAPK pathway; advanced melanoma; metastatic melanoma; reflex testing; stage II; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13092282
  6. Cancers (Basel). 2021 May 10. pii: 2284. [Epub ahead of print]13(9):
    Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations.
    Serena Stamatakos, Giovanni Luca Beretta, Elisabetta Vergani, Matteo Dugo, Cristina Corno, Elisabetta Corna, Stella Tinelli, Simona Frigerio, Emilio Ciusani, Monica Rodolfo, Paola Perego, Laura Gatti.
      Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.
    Keywords:  DHCR24 inhibitor; FASN inhibitor; melanoma; resistance; vemurafenib
    DOI:  https://doi.org/10.3390/cancers13092284
  7. Cancers (Basel). 2021 May 07. pii: 2241. [Epub ahead of print]13(9):
    The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma.
    Elizabeth L Thompson, Jiayi J Hu, Laura J Niedernhofer.
      BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.
    Keywords:  BRAF inhibitors; BRAF mutation; melanoma; resistance; secondary cancer; senescence; senotherapeutics
    DOI:  https://doi.org/10.3390/cancers13092241
  8. Int J Mol Sci. 2021 May 04. pii: 4870. [Epub ahead of print]22(9):
    Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line.
    Dorina Coricovac, Cristina Adriana Dehelean, Iulia Pinzaru, Alexandra Mioc, Oana-Maria Aburel, Ioana Macasoi, George Andrei Draghici, Crina Petean, Codruta Soica, Madalina Boruga, Brigitha Vlaicu, Mirela Danina Muntean.
      Melanoma represents one of the most aggressive and drug resistant skin cancers with poor prognosis in its advanced stages. Despite the increasing number of targeted therapies, novel approaches are needed to counteract both therapeutic resistance and the side effects of classic therapy. Betulinic acid (BA) is a bioactive phytocompound that has been reported to induce apoptosis in several types of cancers including melanomas; however, its effects on mitochondrial bioenergetics are less investigated. The present study performed in A375 human melanoma cells was aimed to characterize the effects of BA on mitochondrial bioenergetics and cellular behavior. BA demonstrated a dose-dependent inhibitory effect in both mitochondrial respiration and glycolysis in A375 melanoma cells and at sub-toxic concentrations (10 μM) induced mitochondrial dysfunction by eliciting a decrease in the mitochondrial membrane potential and changes in mitochondria morphology and localization. In addition, BA triggered a dose-dependent cytotoxic effect characterized by apoptotic features: morphological alterations (nuclear fragmentation, apoptotic bodies) and the upregulation of pro-apoptotic markers mRNA expression (Bax, Bad and Bak). BA represents a viable therapeutic option via a complex modulatory effect on mitochondrial metabolism that might be useful in advanced melanoma or as reliable strategy to counteract resistance to standard therapy.
    Keywords:  OXPHOS; apoptotic markers; betulinic acid; glycolysis; melanoma; mitochondria; mitochondrial membrane potential
    DOI:  https://doi.org/10.3390/ijms22094870
  9. Biomedicines. 2021 May 26. pii: 605. [Epub ahead of print]9(6):
    Melanoma Cell State-Specific Responses to TNFα.
    Su Yin Lim, Sara Alavi, Zizhen Ming, Elena Shklovskaya, Carina Fung, Ashleigh Stewart, Helen Rizos.
      Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as a consequence of T cell activation and can have pleiotropic effects on melanoma response and resistance to PD1 inhibitors. In this study, we examined the influence of TNFα on markers of melanoma dedifferentiation, antigen presentation and immune inhibition in a panel of 40 melanoma cell lines. We report that TNFα signaling is retained in all melanomas but the downstream impact of TNFα was dependent on the differentiation status of melanoma cells. We show that TNFα is a poor inducer of antigen presentation molecules HLA-ABC and HLA-DR but readily induces the PD-L2 immune checkpoint in melanoma cells. Our results suggest that TNFα promotes dynamic changes in melanoma cells that may favor immunotherapy resistance.
    Keywords:  antigen presentation; dedifferentiation; immune checkpoint inhibitors; immunotherapy
    DOI:  https://doi.org/10.3390/biomedicines9060605
  10. Comb Chem High Throughput Screen. 2021 Jun 03.
    Identification of Potential Genes Associated with Vemurafenib Efficacy and Melanoma Prognosis.
    Yue Qi, GuiE Ma.
       OBJECTIVE: This work aimed to investigate the molecular mechanisms underlying the efficacy of vemurafenib as a treatment for melanoma.
    METHODS: The GSE52882 dataset, which includes A375 and A2058 melanoma cell lines treated with vemurafenib and dimethyl sulfoxide (DMSO), and clinical information associated with melanoma patients, were acquired from the Gene Expression Omnibus (GEO) database and University of California Santa Cruz (UCSC), respectively. Functional enrichment analysis, protein-protein interaction (PPI) network construction, sub-module analysis, and transcriptional regulation analysis were performed on overlapping differentially expressed genes (DEGs) identified in both cell lines. Finally, we performed a survival analysis based on the genes identified.
    RESULTS: A total of 447 consistently overlapping DEGs (176 up- and 271 down-regulated DEGs) were screened. Upregulated genes were enriched in pathways of neurotrophin signaling, estrogen signaling, and transcriptional misregulation in cancer. Downregulated DEGs played essential roles in melanogenesis, pathways of cancer, PI3K-Akt signaling pathway, and AMPK signaling pathway. Upregulated (MMP2, JUN, KAT28, and PIK3R3) and downregulated genes (CXCL8, CCND1, IGF1R, and ITGB3) were considered as hub genes in the PPI network. Additionally, PIK3R3 and LEF1 served as key genes in the regulatory network. The overexpression of MMP2 and CXCL8 was associated with a poor prognosis in melanoma patients.
    CONCLUSION: MMP2, CXCL8, PIK3R3, ITGB3, and LEF1 may play roles in the efficacy of vemurafenib treatment in melanoma; for example, MMP2 and PIK3R3 are likely associated with vemurafenib resistance. These findings will contribute to the development of novel therapies for melanoma.
    Keywords:  Melanoma; Vemurafenib; differentially expressed genes; pathway analysis; survival analysis.
    DOI:  https://doi.org/10.2174/1386207324666210603152044
  11. Cancer Chemother Pharmacol. 2021 May 31.
    Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study.
    Lauriane Goldwirt, B Louveau, B Baroudjian, C Allayous, F Jouenne, L Da Meda, L-T Vu, H Sauvageon, F Herms, J Delyon, C Lebbé, S Mourah.
       PURPOSE: Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients.
    METHODS: BRAFV600mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC0-τ and Ctrough) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed.
    RESULTS: Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib Ctrough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE.
    CONCLUSION: In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.
    Keywords:  Dabrafenib; Metastatic melanoma; Pharmacokinetic/pharmacodynamic; Therapeutic drug monitoring; Trametinib
    DOI:  https://doi.org/10.1007/s00280-021-04299-x
  12. J Immunother Cancer. 2021 Jun;pii: e002512. [Epub ahead of print]9(6):
    Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients.
    Alexandre Gérard, Jerome Doyen, Marion Cremoni, Laurent Bailly, Kevin Zorzi, Caroline Ruetsch-Chelli, Vesna Brglez, Alexandra Picard-Gauci, Laura Troin, Vincent L M Esnault, Thierry Passeron, Henri Montaudié, Barbara Seitz-Polski.
       BACKGROUND: Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.
    METHODS: Previously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (NCT02799901). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.
    RESULTS: Seventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2-28.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-α and interferon-γ (IFN-γ) (1136 pg/mL vs 5558 pg/mL, p<0.0001; and 3894 pg/mL vs 17 129 pg/mL, p=0.02, respectively). Responders exhibited increasing cytokine levels from baseline to week 6. Non-responders had lower interleukin 17A (IL-17A) levels at baseline than responders (7 pg/mL vs 32 pg/mL, p=0.03), and lower IFN-γ levels at week 6 (3.3 ng/mL vs 14.5 ng/mL, p=0.03). A lower level of IL-17A at week 2 and a lower level of IFN-γ at week 6 correlated with worse PFS (p=0.04 and p=0.04 respectively). At baseline, patients who developed irAEs had higher IL-6 levels (19.3 ng/mL vs 9.2 ng/mL, p=0.03) and higher IL-17A levels (52.5 pg/mL vs 2.5 pg/mL, p=0.009) than those without irAEs.
    CONCLUSIONS: Our findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy.
    Keywords:  cellular; cytokines; immunity; immunocompetence; immunotherapy; programmed cell death 1 receptor
    DOI:  https://doi.org/10.1136/jitc-2021-002512
  13. BMC Cancer. 2021 May 29. 21(1): 641
    The role of FoxP3+ regulatory T cells and IDO+ immune and tumor cells in malignant melanoma - an immunohistochemical study.
    Satu Salmi, Anton Lin, Benjamin Hirschovits-Gerz, Mari Valkonen, Niina Aaltonen, Reijo Sironen, Hanna Siiskonen, Sanna Pasonen-Seppänen.
       BACKGROUND: FoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM). Recent studies have reported that IDO expression correlates with poor prognosis and greater Breslow's depth, but results concerning the role of FoxP3+ Tregs in CM have been controversial. Furthermore, the correlation between IDO and Tregs has not been substantially studied in CM, although IDO is known to be an important regulator of Tregs activity.
    METHODS: We investigated the associations of FoxP3+ Tregs, IDO+ tumor cells and IDO+ stromal immune cells with tumor stage, prognostic factors and survival in CM. FoxP3 and IDO were immunohistochemically stained from 29 benign and 29 dysplastic nevi, 18 in situ -melanomas, 48 superficial and 62 deep melanomas and 67 lymph node metastases (LNMs) of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells, and the coverage and intensity of IDO+ tumor cells were analysed.
    RESULTS: The number of FoxP3+ Tregs and IDO+ stromal immune cells were significantly higher in malignant melanomas compared with benign lesions. The increased expression of IDO in melanoma cells was associated with poor prognostic factors, such as recurrence, nodular growth pattern and increased mitotic count. Furthermore, the expression of IDO in melanoma cells was associated with reduced recurrence-free survival. We further showed that there was a positive correlation between IDO+ tumor cells and FoxP3+ Tregs.
    CONCLUSIONS: These results indicate that IDO is strongly involved in melanoma progression. FoxP3+ Tregs also seems to contribute to the immunosuppressive TME in CM, but their significance in melanoma progression remains unclear. The positive association of FoxP3+ Tregs with IDO+ melanoma cells, but not with IDO+ stromal immune cells, indicates a complex interaction between IDO and Tregs in CM, which demands further studies.
    Keywords:  FoxP3; IDO; Immunosuppression; Melanoma; Regulatory T cells; TME
    DOI:  https://doi.org/10.1186/s12885-021-08385-4
  14. Biomedicines. 2021 May 26. pii: 607. [Epub ahead of print]9(6):
    Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications.
    Alice Indini, Francesco Grossi, Mario Mandalà, Daniela Taverna, Valentina Audrito.
      Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients' selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.
    Keywords:  immunometabolism; immunotherapy; melanoma; metabolic reprogramming; soluble factors; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines9060607
  15. Cancers (Basel). 2021 May 15. pii: 2393. [Epub ahead of print]13(10):
    BRAF/EZH2 Signaling Represses miR-129-5p Inhibition of SOX4 Thereby Modulating BRAFi Resistance in Melanoma.
    Kathleen Gebhardt, Bayram Edemir, Elisabeth Groß, Linda Nemetschke, Stefanie Kewitz-Hempel, Rose K C Moritz, Cord Sunderkötter, Dennis Gerloff.
      Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.
    Keywords:  BRAF mutation; melanoma; miRNAs; therapy resistance
    DOI:  https://doi.org/10.3390/cancers13102393
  16. Cancer Manag Res. 2021 ;13 4181-4189
    USP8 is a Novel Therapeutic Target in Melanoma Through Regulating Receptor Tyrosine Kinase Levels.
    Baoxue Duan, Changying Wang, Zeng Liu, Xiaoyu Yang.
       Introduction: The hyperactivation of receptor tyrosine kinase (RTK)-mediated pathways plays an important role in melanoma progression and resistance to therapy. The ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme and its inhibition induces degradation of RTKs. This work explored the expression and role of USP8 in melanoma.
    Methods: ELISA and qPCR were performed to assess USP8 expression in melanoma tissues and cells, as well as their normal counterparts. Cellular proliferation, migration and apoptosis assays were performed to determine USP8 functions in three melanoma cell lines. Western blot was performed to analyze RTK signaling in melanoma cells after USP8 inhibition.
    Results: mRNA and protein level of USP8 were higher in melanoma cells than normal melanocytes. Higher USP8 expression was also found in tumors in the majority of melanoma patients. USP8 expression was not associated with clinicopathological features, such as age, disease stage, histology, ulceration and BRAF status. Functional analysis demonstrated that USP8 overexpression promoted melanoma cell activities and alleviated the inhibitory effects of therapeutic drugs. In contrast, USP8 knockdown suppressed melanoma cell growth, survival and migration, and augmented the inhibitory effects of therapeutic drugs. Mechanism studies revealed that USP8 inhibition remarkably reduced the expression level of multiple oncogenic RTKs, including c-Met, Kit, EGFR and GPCR. Consistently, RTK-mediated downstream pathways were disrupted in USP8-depleted cells, leading to the increased level of pro-apoptotic proteins and decreased level of anti-apoptotic proteins.
    Conclusion: Inhibition of USP8 activity is a novel sensitizing strategy to overcome therapy resistance in melanoma.
    Keywords:  USP8; melanoma; receptor tyrosine kinase; therapy resistance
    DOI:  https://doi.org/10.2147/CMAR.S300195
  17. Cancers (Basel). 2021 May 11. pii: 2293. [Epub ahead of print]13(10):
    Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model.
    Shuyang S Qin, Booyeon J Han, Alyssa Williams, Katherine M Jackson, Rachel Jewell, Alexander C Chacon, Edith M Lord, David C Linehan, Minsoo Kim, Alexandre Reuben, Scott A Gerber, Peter A Prieto.
      Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.
    Keywords:  PD-L1; immunomodulation; metastatic melanoma; tumor heterogeneity; tumor microenvironment; tumor models
    DOI:  https://doi.org/10.3390/cancers13102293
  18. Int J Mol Sci. 2021 May 10. pii: 5034. [Epub ahead of print]22(9):
    Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism.
    Iwona Karwaciak, Anna Sałkowska, Kaja Karaś, Jarosław Dastych, Marcin Ratajewski.
      Melanoma cells are resistant to most anticancer chemotherapeutics. Despite poor response rates and short-term efficacy, chemotherapy remains the main approach to treating this cancer. The underlying mechanisms of the intrinsic chemoresistance of melanoma remain unclear, but elucidating these mechanisms is important to improve the efficacy of chemotherapy regimens. Increasing evidence suggests that sirtuin 2 (SIRT2) plays a key role in the response of melanoma cells to chemotherapeutics; thus, in the present study, we evaluated the impact of shRNA-mediated and pharmacological inhibition of SIRT2 on the sensitivity of melanoma cells to cisplatin, which is used in several regimens to treat melanoma patients. We found that cells with SIRT2 inhibition revealed increased sensitivity to cisplatin and exhibited increased accumulation of γ-H2AX and reduced EGFR-AKT-RAF-ERK1/2 (epidermal growth factor receptor-protein B kinase-RAF kinase-extracellular signal-regulated kinase 1/2) pathway signaling compared to control cells. Thus, our results show that sirtuin 2 inhibition increased the in vitro efficacy of cisplatin against melanoma cells.
    Keywords:  EGFR; SIRT2; cisplatin; melanoma; resistance
    DOI:  https://doi.org/10.3390/ijms22095034
  19. Int J Mol Sci. 2021 May 26. pii: 5636. [Epub ahead of print]22(11):
    Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells.
    Marina Pisano, Maria Antonietta Dettori, Davide Fabbri, Giovanna Delogu, Giuseppe Palmieri, Carla Rozzo.
      Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds-namely, compounds 11 and 12-were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 ± 0.5 μM for 11 and 2.0 ± 0.7 μM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed long-lasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.
    Keywords:  apoptosis; curcumin analogs; hydroxylated biphenyl; melanoma
    DOI:  https://doi.org/10.3390/ijms22115636
  20. Immun Inflamm Dis. 2021 Jun 02.
    Identification and validation of immune-related lncRNA prognostic signatures for melanoma.
    Bo Xiao, Liyan Liu, Aoyu Li, Pingxiao Wang, Cheng Xiang, Hui Li, Tao Xiao.
       INTRODUCTION: Melanoma is a highly aggressive malignant skin tumor as well as the primary reason for skin cancer-specific deaths. We first identified immune-related long noncoding RNA (lncRNA) prognostic signature and found potential immunotherapeutic targets for melanoma cancer.
    METHODS: RNA-seq data and clinical features of melanoma samples were obtained from The Cancer Genome Atlas. Samples of melanoma were randomly assigned to the training and testing cohort. The immune-related lncRNA signature was then obtained via using univariate, LASSO, and multivariate Cox analysis of patients in the training cohort. Eight significant immune-related lncRNA signature was then subsequently obtained through correlation analysis between immune-related genes and lncRNAs. The association between risk score and immune cell infiltration was finally assessed using TIMER and CIBERSORT.
    RESULTS: Three hundred and fifty-six immune-related lncRNAs were obtained. Among them, eight immune-related lncRNAs were identified to build a prognostic risk signature model. The model's performance was then confirmed using the Kaplan-Meier curves, risk plots, and time-dependent receiver-operating characteristic curves in the training cohort. The risk score was identified and confirmed as an independent prognostic factor through univariate and multivariate Cox regression analyses. These results were further verified in the testing and whole cohorts. CIBERSORT algorithm showed that the infiltration levels of T cells CD8, M1 macrophages, plasma cells, T cells CD4 memory activated, T cells gamma delta, and mast cells activated were significantly lower in the high-risk group while the infiltration level of macrophages M0 was significantly lower in the low-risk group.
    CONCLUSION: The immune-related lncRNA signature offers prognostic markers and potential immunotherapeutic targets for melanoma.
    Keywords:  TCGA; immune; lncRNAs; melanoma; prognosis
    DOI:  https://doi.org/10.1002/iid3.468
  21. J Clin Med. 2021 May 24. pii: 2259. [Epub ahead of print]10(11):
    Learning from Embryogenesis-A Comparative Expression Analysis in Melanoblast Differentiation and Tumorigenesis Reveals miRNAs Driving Melanoma Development.
    Lisa Linck-Paulus, Lisa Lämmerhirt, Daniel Völler, Katharina Meyer, Julia C Engelmann, Rainer Spang, Norbert Eichner, Gunter Meister, Silke Kuphal, Anja Katrin Bosserhoff.
      Malignant melanoma is one of the most dangerous tumor types due to its high metastasis rates and a steadily increasing incidence. During tumorigenesis, the molecular processes of embryonic development, exemplified by epithelial-mesenchymal transition (EMT), are often reactivated. For melanoma development, the exact molecular differences between melanoblasts, melanocytes, and melanoma cells are not completely understood. In this study, we aimed to identify microRNAs (miRNAs) that promote melanoma tumorigenesis and progression, based on an in vitro model of normal human epidermal melanocyte (NHEM) de-differentiation into melanoblast-like cells (MBrCs). Using miRNA-sequencing and differential expression analysis, we demonstrated in this study that a majority of miRNAs have an almost equal expression level in NHEMs and MBrCs but are significantly differentially regulated in primary tumor- and metastasis-derived melanoma cell lines. Further, a target gene analysis of strongly regulated but functionally unknown miRNAs yielded the implication of those miRNAs in many important cellular pathways driving malignancy. We hypothesize that many of the miRNAs discovered in our study are key drivers of melanoma development as they account for the tumorigenic potential that differentiates melanoma cells from proliferating or migrating embryonic cells.
    Keywords:  embryogenesis; melanoblasts; melanoma; miRNAs
    DOI:  https://doi.org/10.3390/jcm10112259
  22. Magy Onkol. 2021 Jun 03. 65(2): 149-156
    [Molecular background of BRAF inhibitor induced resistance in BRAFV600E mutant melanoma cell lines].
    István Szász, Viktória Koroknai, Laura Vízkeleti, Margit Balázs.
      Target-specific inhibition of the BRAFV600E mutant protein has been a major breakthrough in the treatment of metastatic cutaneous melanoma. However, the success of therapies is significantly overshadowed by the development of resistance. Understanding the molecular mechanisms associated with acquired resistance is an important step to increase the effectiveness of melanoma treatment. Our aim was to elucidate the molecular differences underlying the development of drug resistance using a mutant BRAF protein inhibitor (vemurafenib analogue: PLX4720) in BRAFV600E mutant melanoma cell lines. We developed four BRAF inhibitor-resistant cell lines and examined the effect of BRAF inhibitor "withdrawal" on cell division. ArrayCGH was used to define genetic, and Affymetrix HumanGene 1.0 microarray to monitor gene expression alterations between the sensitive and resistant cell lines. Protein expression was determined using Proteome Profiler Human XL Oncology Array. We found that withdrawal of the inhibitor reduces cell proliferation in the resistant cells. The invasive potential of the resistant cells increased. Using genomic and proteomic methods we described new molecular alterations associated with acquired resistance.
  23. Int J Mol Sci. 2021 May 17. pii: 5265. [Epub ahead of print]22(10):
    From Melanocytes to Melanoma Cells: Characterization of the Malignant Transformation by Four Distinctly Different Melanin Fluorescence Spectra (Review).
    Dieter Leupold, Lutz Pfeifer, Maja Hofmann, Andrea Forschner, Gerd Wessler, Holger Haenssle.
      The melanin fluorescence emitted by pigment cells of the human skin has been a central research topic for decades, because melanin, on the one hand, protects against (solar) radiation in the near-UV range, whereas on the other hand, melanocytes are the starting point for the malignant transformation into melanoma. Until recently, however, melanin fluorescence was not accessible in the context of conventional spectroscopy, because it is ultraweak and is overshadowed by the more intense so-called autofluorescence of endogenous fluorophores. The advent of a new method of laser spectroscopy has made this melanin fluorescence measurable in vivo. A stepwise two-photon absorption with 800 nm photons is used, which more selectively excites melanin (dermatofluoroscopy). Our review summarizes the experimental results on melanin fluorescence of the four types of cutaneous pigment cells from healthy and malignant tissues. Outstanding is the finding that different types of melanocytes (i.e., melanocytes of common nevi, versus dysplastic nevi or versus melanoma cells) show characteristically different fluorescence spectra. The possibilities of using this melanin fluorescence for melanoma diagnosis are shown. Moreover, the uniform fluorescence spectra emitted by different melanoma subtypes are essential. Conclusions are drawn about the molecular processes in the melanosomes that determine fluorescence. Finally, experimental suggestions for further investigations are given.
    Keywords:  dermatofluoroscopy; dysplastic nevi; melanin fluorescence; melanoma subtypes
    DOI:  https://doi.org/10.3390/ijms22105265
  24. Cancer Res. 2021 Jun 01. 81(11): 2918-2929
    LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells.
    Shujun Han, Yuwei Yan, Yibo Ren, Yiming Hu, Yan Wang, Lei Chen, Zhe Zhi, Yan Zheng, Yongping Shao, Jiankang Liu.
      The long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival. However, whether SAMMSON regulates the response of mutant BRAF melanoma cells to RAF inhibitors remains unknown. In this work, we showed that SAMMSON is rapidly induced upon inhibition of ERK signaling, and SAMMSON overexpression conferred resistance to vemurafenib-induced cytotoxicity in melanoma cells. SOX10 mediated transcriptional induction of SAMMSON by vemurafenib, and SOX10 sumoylation at K55 was essential for this function. In addition, depletion of SAMMSON activated p53 signaling, which is dependent on the SAMMSON-interacting protein CARF. Depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo, while CARF knockdown reversed the enhanced sensitivity. In summary, these findings suggest that SAMMSON may function as a new mediator of adaptive resistance to RAF inhibitors in melanoma by modulating CARF-p53 signaling. SIGNIFICANCE: This study highlights the role of a SAMMSON/CARF/p53 signaling axis in modulating the adaptive resistance of mutant BRAF melanoma to RAF inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3145
  25. Curr Top Dev Biol. 2021 ;pii: S0070-2153(21)00028-4. [Epub ahead of print]145 313-348
    Xenopus, an emerging model for studying pathologies of the neural crest.
    Laura Medina-Cuadra, Anne H Monsoro-Burq.
      Neural crest cells are a multipotent embryonic stem cell population that emerges from the lateral border of the neural plate after an epithelium-to-mesenchyme transition. These cells then migrate extensively in the embryo and generate a large variety of differentiated cell types and tissues. Alterations in almost any of the processes involved in neural crest development can cause severe congenital defects in humans. Moreover, the malignant transformation of one of the many neural crest derivatives, during childhood or in adults, can cause the development of aggressive tumors prone to metastasis such as melanoma and neuroblastoma. Collectively these diseases are called neurocristopathies. Here we review how a variety of approaches implemented using the amphibian Xenopus as an experimental model have shed light on the molecular basis of numerous neurocristopathies, and how this versatile yet underused vertebrate animal model could help accelerate discoveries in the field. Using the current framework of the neural crest gene regulatory network, we review the pathologies linked to defects at each step of neural crest formation and highlight studies that have used the Xenopus model to decipher the cellular and molecular aspects of neurocristopathies.
    Keywords:  Cell migration; Craniofacial development; Epithelium-to-mesenchyme transition; Gene regulatory network; Human rare disease; Melanoma; Neural crest; Neuroblastoma; Neurocristopathies; Xenopus laevis; Xenopus tropicalis
    DOI:  https://doi.org/10.1016/bs.ctdb.2021.03.002
  26. Mol Oncol. 2021 Jun 03.
    The pleiotropic role of circular and long non-coding RNAs in cutaneous melanoma.
    Barbara Montico, Giorgio Giurato, Giovanni Pecoraro, Annamaria Salvati, Alessia Covre, Francesca Colizzi, Agostino Steffan, Alessandro Weisz, Michele Maio, Luca Sigalotti, Elisabetta Fratta.
      Cutaneous melanoma (CM) is a very aggressive disease, often characterized by unresponsiveness to conventional therapies and high mortality rates world-wide. The identification of the activating BRAFV600 mutations in approximately 50% of CM patients has recently fuelled the development of novel small molecule inhibitors that specifically target BRAFV600 -mutant CM. In addition, a major progress in CM treatment has been made by monoclonal antibodies that regulate the immune checkpoint inhibitors. However, although target-based therapies and immunotherapeutic strategies have yielded promising results, CM treatment remains a major challenge. In the last decade, accumulating evidence points to the aberrant expression of different types of non-coding RNAs (ncRNAs) in CM. While studies on microRNAs have grown exponentially leading to significant insights on CM biology, the role of circular RNAs (circRNAs) and long non coding RNAs (lncRNAs) in this tumor is less understood, and much remains to be discovered. Here, we summarize and critically review the available evidence on the molecular functions of circRNAs and lncRNAs in BRAFV600 -mutant CM and CM immunogenicity, providing recent updates on their functional role in targeted-therapy and immunotherapy resistance. In addition, we also include an evaluation of several algorithms and databases for prediction and validation of circRNAs and lncRNAs functional interactions.
    Keywords:  Circular RNAs; cutaneous melanoma; immunotherapy; long non-coding RNAs; targeted therapy
    DOI:  https://doi.org/10.1002/1878-0261.13034
  27. Int J Mol Sci. 2021 May 17. pii: 5283. [Epub ahead of print]22(10):
    Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape.
    Veronica Romano, Immacolata Belviso, Alessandro Venuta, Maria Rosaria Ruocco, Stefania Masone, Federica Aliotta, Giuseppe Fiume, Stefania Montagnani, Angelica Avagliano, Alessandro Arcucci.
      Cutaneous melanoma (CM) tissue represents a network constituted by cancer cells and tumor microenvironment (TME). A key feature of CM is the high structural and cellular plasticity of TME, allowing its evolution with disease and adaptation to cancer cell and environmental alterations. In particular, during melanoma development and progression each component of TME by interacting with each other and with cancer cells is subjected to dramatic structural and cellular modifications. These alterations affect extracellular matrix (ECM) remodelling, phenotypic profile of stromal cells, cancer growth and therapeutic response. The stromal fibroblast populations of the TME include normal fibroblasts and melanoma-associated fibroblasts (MAFs) that are highly abundant and flexible cell types interacting with melanoma and stromal cells and differently influencing CM outcomes. The shift from the normal microenvironment to TME and from normal fibroblasts to MAFs deeply sustains CM growth. Hence, in this article we review the features of the normal microenvironment and TME and describe the phenotypic plasticity of normal dermal fibroblasts and MAFs, highlighting their roles in normal skin homeostasis and TME regulation. Moreover, we discuss the influence of MAFs and their secretory profiles on TME remodelling, melanoma progression, targeted therapy resistance and immunosurveillance, highlighting the cellular interactions, the signalling pathways and molecules involved in these processes.
    Keywords:  fibroblasts; melanoma; melanoma-associated fibroblasts; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms22105283
  28. Int J Mol Sci. 2021 May 12. pii: 5115. [Epub ahead of print]22(10):
    Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?
    Stephanie McKenna, Lucía García-Gutiérrez.
      Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
    Keywords:  DNA methylation; RASSF1A; melanoma; resistance; targeted therapy; tumour suppressor
    DOI:  https://doi.org/10.3390/ijms22105115
  29. Cancers (Basel). 2021 May 10. pii: 2277. [Epub ahead of print]13(9):
    Neuroendocrine Factors in Melanoma Pathogenesis.
    Cristian Scheau, Carmen Draghici, Mihaela Adriana Ilie, Mihai Lupu, Iulia Solomon, Mircea Tampa, Simona Roxana Georgescu, Ana Caruntu, Carolina Constantin, Monica Neagu, Constantin Caruntu.
      Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.
    Keywords:  melanoma; neurohormones; neuropeptides; neurotransmitters; stress
    DOI:  https://doi.org/10.3390/cancers13092277
  30. Front Immunol. 2021 ;12 654463
    A Small Molecule Antagonist of PD-1/PD-L1 Interactions Acts as an Immune Checkpoint Inhibitor for NSCLC and Melanoma Immunotherapy.
    Yuanyuan Wang, Tingxuan Gu, Xueli Tian, Wenwen Li, Ran Zhao, Wenqian Yang, Quanli Gao, Tiepeng Li, Jung-Hyun Shim, Chengjuan Zhang, Kangdong Liu, Mee-Hyun Lee.
      Immune checkpoint inhibitors, such as monoclonal antibodies targeting programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1), have achieved enormous success in the treatment of several cancers. However, monoclonal antibodies are expensive to produce, have poor tumor penetration, and may induce autoimmune side effects, all of which limit their application. Here, we demonstrate that PDI-1 (also name PD1/PD-L1 inhibitor 1), a small molecule antagonist of PD-1/PD-L1 interactions, shows potent anti-tumor activity in vitro and in vivo and acts by relieving PD-1/PD-L1-induced T cell exhaustion. We show that PDI-1 binds with high affinity to purified human and mouse PD-1 and PD-L1 proteins and is a competitive inhibitor of human PD-1/PD-L1 binding in vitro. Incubation of ex vivo activated human T cells with PDI-1 enhanced their cytotoxicity towards human lung cancer and melanoma cells, and concomitantly increased the production of granzyme B, perforin, and inflammatory cytokines. Luciferase reporter assays showed that PDI-1 directly increases TCR-mediated activation of NFAT in a PD-1/PD-L1-dependent manner. In two syngeneic mouse tumor models, the intraperitoneal administration of PDI-1 reduced the growth of tumors derived from human PD-L1-transfected mouse lung cancer and melanoma cells; increased and decreased the abundance of tumor-infiltrating CD8+ and FoxP3+ CD4+ T cells, respectively; decreased the abundance of PD-L1-expressing tumor cells, and increased the production of inflammatory cytokines. The anti-tumor effect of PDI-1 in vivo was comparable to that of the anti-PD-L1 antibody atezolizumab. These results suggest that the small molecule inhibitors of PD-1/PD-L1 may be effective as an alternative or complementary immune checkpoint inhibitor to monoclonal antibodies.
    Keywords:  PD-1/PD-L1; PD-1/PD-L1 inhibitor 1; PDI-1; T cell activation; immunotherapy; small molecule compound
    DOI:  https://doi.org/10.3389/fimmu.2021.654463
  31. Cells. 2021 May 28. pii: 1334. [Epub ahead of print]10(6):
    CDK4/6 Inhibitors in Melanoma: A Comprehensive Review.
    Mattia Garutti, Giada Targato, Silvia Buriolla, Lorenza Palmero, Alessandro Marco Minisini, Fabio Puglisi.
      Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.
    Keywords:  Abemaciclib; CDK4; CDK4/6; CDK6; Palbociclib; Ribociclib; melanoma
    DOI:  https://doi.org/10.3390/cells10061334
  32. Cancer Genet. 2021 May 18. pii: S2210-7762(21)00108-3. [Epub ahead of print]256-257 91-99
    Mitochondrial DNA polymorphisms and biogenesis genes in primary and metastatic uveal melanoma cell lines.
    Lata Singh, Shari R Atilano, Martine J Jager, M Cristina Kenney.
       PURPOSE: This study was designed to identify mitochondrial (mt) DNA variations in primary and metastatic uveal melanoma (UM) cell lines and their relation with cell metabolism to gain insight into metastatic progression.
    METHOD: The entire mtDNA genomes were sequenced using Sanger sequencing from two primary UM cell lines (92.1 and MEL270) and two cell lines (OMM2.3 and OMM2.5) derived from liver metastases of the MEL270 patient. The mtDNA copy numbers determined by the ratio of nDNA versus mtDNA. qRT-PCR was used to evaluate expression levels of mitochondrial biogenesis genes.
    RESULTS: Sequencing showed that cell line MEL270 and metastases-derived OMM2.3 and OMM2.5 cell lines had homoplasmic single nucleotide polymorphisms (SNPs) representing J1c7a haplogroup, whereas 92.1 cells had mtDNA H31a haplogroup. mtDNA copy numbers were significantly higher in primary cell lines. The metastatic UM cells showed down-regulation of POLG, TFAM, NRF-1 and SIRT1 compared to their primary MEL270 cells. PGC-1α was downregulated in 92.1 and upregulated in MEL270, OMM2.3 and OMM2.5.
    CONCLUSIONS: Our finding suggests that within metastatic cells, the heteroplasmic SNPs, copy numbers and mitochondrial biogenesis genes are modulated differentially compared to their primary UM cells. Therefore, investigating pathogenic mtDNA variants associated with cancer metabolic susceptibility may provide future therapeutic strategies in metastatic UM.
    Keywords:  Biogenesis; Eye disease; Mitochondria; Ocular oncology; Uveal melanoma
    DOI:  https://doi.org/10.1016/j.cancergen.2021.05.002
  33. Cancers (Basel). 2021 May 18. pii: 2464. [Epub ahead of print]13(10):
    Evaluation of a Three-Marker Panel for the Detection of Uveal Melanoma Metastases: A Single-Center Retrospective Analysis.
    Zenan Lin, Daniela Süsskind.
      Blood-based B-cell activating factor (BAFF), growth differentiation factor-15 (GDF-15) and osteopontin (OPN) have been identified to be promising biomarkers for the metastases of uveal melanoma (UM). This study intended to assess their kinetics and to evaluate their significance as a three-marker panel. A group of 36 UM patients with and 137 patients without metastases were included in the study. Their plasma OPN levels were measured by ELISA; serum BAFF and GDF-15 levels were determined with a Luminex MAGPIX system. Receiver operating characteristic (ROC) analysis was performed to calculate the cutoff values of the three markers for identifying the patients with metastases. The ability to identify patients with metastases was compared between the single markers and the combination as a three-marker panel. By using the Student's t-test, we also investigated the kinetic changes of the levels of BAFF, GDF-15 and OPN across six periods (i.e., 0-6 months, 6-12 months, 12-18 months, 18-24 months, >24 months and post-metastasis) before the imaging diagnosis of metastases. By maximizing the Youden's index, the serum GDF-15 level of 1209 pg/mL and the plasma OPN level of 92 ng/mL were identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. The three-marker panel offered a better performance in distinguishing patients with metastases, with an area under the curve of 0.802, than any single biomarker. Increasing trends of the levels of three biomarkers were observed in the two-year period before the imaging diagnosis of metastases. The combined panel of BAFF, GDF-15 and OPN might be a utilizable implementation for the detection of UM metastases. In the bioinformatics study with two external datasets, the high expression of gene BAFF and GDF-15 in primary UM tissues was identified to be associated with poor overall survival rates. As the current work is a single-center retrospective study, more well-designed prospective investigations employing larger cohorts are urgently needed to validate our findings.
    Keywords:  B-cell activating factor; growth differentiation factor-15; metastasis; multi-biomarker panel; osteopontin; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13102464
  34. Life (Basel). 2021 May 05. pii: 424. [Epub ahead of print]11(5):
    Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas.
    Jiri Vachtenheim, Lubica Ondrušová.
      Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly BRAF and NRAS). Both these mutated oncogenes strongly activate the MAPK (MEK/ERK) pathway. Therefore, specific inhibitors of these oncoproteins or MAPK pathway components or their combination have been used for tumor eradication. After a good initial response, resistant cells develop almost universally and need the drug for further expansion. Multiple mechanisms, sometimes very distant from the MAPK pathway, are responsible for the development of resistance. Here, we review many of the mechanisms causing resistance and leading to the dismal final outcome of mutated BRAF and NRAS therapy. Very heterogeneous events lead to drug resistance. Due to this, each individual mechanism would be in fact needed to be determined for a personalized therapy to treat patients more efficiently and causally according to molecular findings. This procedure is practically impossible in the clinic. Other approaches are therefore needed, such as combined treatment with more drugs simultaneously from the beginning of the therapy. This could eradicate tumor cells more rapidly and greatly diminish the possibility of emerging mechanisms that allow the evolution of drug resistance.
    Keywords:  BRAF; NRAS; drug resistance; melanoma; phenotype switching
    DOI:  https://doi.org/10.3390/life11050424
  35. Pathol Res Pract. 2021 May 13. pii: S0344-0338(21)00125-4. [Epub ahead of print]223 153464
    CD63 expression in metastatic melanoma and melanocytic nevi in lymph nodes.
    Odille Mejia, Thomas Vazquez, John Alexis.
      Lymph node status remains one of the most important determinants for prognosis in patients with invasive malignant melanoma. Immunohistochemical stains are routinely employed in the histopathologic evaluation of sentinel lymph nodes removed for staging in patients with melanoma. Histologic analysis may reveal the presence of incidental benign melanocytic nevus cell inclusions (BMNCI), which are critical to distinguish from metastatic melanoma (MM). Our study assesses the utility of NK1 C3 (CD63) immunohistochemical staining in distinguishing between MM and BMNCI in sentinel lymph nodes. We found no difference in staining of MM and BMNCI, precluding its usefulness in differentiating between benign and malignant melanocytes. Thus CD63 lacks specificity when facing challenging cases requiring distinction between benign and malignant melanocytic cells; however, in combination with other immunohistochemical antibodies, CD63 may be useful in supporting melanocytic differentiation. Distinguishing MM and BMNCI continues to be a diagnostic challenge at times. Further research is needed to identify potentially useful markers to provide better diagnostic utility when evaluating lymph node biopsies in patients with melanoma.
    Keywords:  CD63; Immunohistochemistry; Lymph node; Melanoma; Nevus
    DOI:  https://doi.org/10.1016/j.prp.2021.153464
  36. Exp Dermatol. 2021 Jun 03.
    Visible light and human skin pigmentation: The importance of skin phototype.
    Hugo Moreiras, Clare O'Connor, Mike Bell, Desmond J Tobin.
      Melanin is synthesised within melanocytes and transferred to keratinocytes in human skin, thereby regulating skin colour and protecting skin cells against UVR-induced damage. We commonly divide human skin into six phototypes (SPT)-I to -VI (Fitzpatrick scale) according to the skin's tanning response to UVR. In this pilot study, we investigated the impact of UVR (maximum 311nm), blue (peak 450nm) and green visible light (peak 530nm) on melanin production and type in healthy human skin histocultures (SPT-I, -II and -III). UVR, blue and green light stimulated a surface tanning response in SPT-II and -III, but not SPT-I. Using the Warthin-Starry stain for sensitive melanin detection, all three light treatments induced melanogenesis in SPT-II and -III skin. Surprisingly, blue and green light (but not UVR) stimulated melanin synthesis in SPT-I skin. Moreover, melanin synthesis induced by blue and green visible light in SPT-I, SPT-II, and SPT-III skin was not associated with a detectable increase in DNA damage or cell apoptosis. By contrast, both responses were detected after UVR. These data suggest that blue and green visible light can stimulate melanin production in fair-skinned individuals without, at least some of, the harmful consequences of UVR-induced pigmentation. We are currently examining the molecular basis of UVR-independent melanogenesis in fair skin.
    Keywords:  blue light; green light; melanin; photo-biomodulation; skin phototypes; ultra-violet radiation
    DOI:  https://doi.org/10.1111/exd.14400
  37. Cancers (Basel). 2021 May 18. pii: 2440. [Epub ahead of print]13(10):
    Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants.
    Francesco Spagnolo, Bruna Dalmasso, Enrica Tanda, Miriam Potrony, Susana Puig, Remco van Doorn, Ellen Kapiteijn, Paola Queirolo, Hildur Helgadottir, Paola Ghiorzo.
      Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/-MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/-MEKi with an expected rate derived from phase III trials and "real-world" studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60-0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62-0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/-MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.
    Keywords:  BRAF inhibitors; CDKN2A; MEK inhibitors; genetic counseling; melanoma; melanoma susceptibility; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13102440
  38. Acta Oncol. 2021 Jun 04. 1-9
    Plasma circulating cell free messenger RNA as a potential biomarker of melanoma.
    Michael Itak Ita, Jiang Huai Wang, Noel Fanning, George Kaar, Chris Lim, Henry Paul Redmond.
       BACKGROUND: Blood borne cell free nucleic acids are increasingly emerging as significant non-invasive adjuncts to current methods of disease status evaluation in cancer patients. In this study, we sought to examine whether significant differences exist in the plasma transcriptomic profile of advanced melanoma patients with a high disease burden compared to patients with a low disease burden or therapeutic response.
    METHODS: Pathway focussed gene expression analysis was performed using cDNA derived from the plasma circulating cell free messenger ribonucleic acid (ccfmRNA) samples of twenty-two patients with advanced melanoma. Patients were assessed with paired blood sample collection and CT scan assessments at baseline and at 3 months follow up.
    RESULTS: We identified several genes which were significantly over-expressed in patients with a low disease burden or therapeutic response; BCL2L1, CXCL9, IDO1, IL13, MIF, MYD88 and TLR4 (p ≤ 0.001, versus high disease burden). There was an increase in the magnitude of fold change (2^ (-dd CT)) of BCL2L1 (p = 0.031), CCL4 (p = 0.001), CCL5 (p = 0.043), CXCL9 (p = 0.012), GZMB (p = 0.023) and TNFSF10 (p = 0.039) genes in patients with therapeutic response at 3 months follow up assessment relative to baseline assessment. Moreover, in stage IV melanoma patients with brain metastases, CCL18, CCR1, CCR4, CD274, CSF2, EGF, and PTGS2 genes were significantly over-expressed (p < 0.001, versus patients without melanoma brain metastasis).
    CONCLUSION: Significant differences were observed in the plasma transcriptomic profile between the various melanoma patient groups, and we postulate that these differences may be exploited to identify novel therapeutic targets or biomarkers relevant to melanoma.
    Keywords:  Melanoma; biomarkers; circulating cell free messenger RNA
    DOI:  https://doi.org/10.1080/0284186X.2021.1928749
  39. Med Clin North Am. 2021 Jul;pii: S0025-7125(21)00043-2. [Epub ahead of print]105(4): 643-661
    Recognition, Staging, and Management of Melanoma.
    Sarem Rashid, Hensin Tsao.
      Melanoma accounts for approximately 1% of all skin cancers but contributes to almost all skin cancer deaths. The developing picture suggests that melanoma phenotypes are driven by epigenetic mechanisms that reflect a complex interplay between genotype and environment. Furthermore, the growing consensus is that current classification standards, notwithstanding pertinent clinical history and appropriate biopsy, fall short of capturing the vast complexity of the disease. This article summarizes the current understanding of the clinical picture of melanoma, with a focus on the tremendous breakthroughs in molecular classification and therapeutics.
    Keywords:  Heterogeneity; Management; Melanoma; Staging; Treatment
    DOI:  https://doi.org/10.1016/j.mcna.2021.04.005
  40. Genes (Basel). 2021 May 31. pii: 849. [Epub ahead of print]12(6):
    PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation.
    Stephanie Jonuscheit, Tina Jost, Fritzi Gajdošová, Maximilian Wrobel, Markus Hecht, Rainer Fietkau, Luitpold Distel.
      (1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment.
    Keywords:  PARP; ionizing radiation; kinase inhibitors
    DOI:  https://doi.org/10.3390/genes12060849
  41. Cancers (Basel). 2021 May 07. pii: 2243. [Epub ahead of print]13(9):
    The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma.
    Jean-Noël Hubert, Voreak Suybeng, Maxime Vallée, Tiffany M Delhomme, Eve Maubec, Anne Boland, Delphine Bacq, Jean-François Deleuze, Fanélie Jouenne, Paul Brennan, James D McKay, Marie-Françoise Avril, Brigitte Bressac-de Paillerets, Estelle Chanudet.
      Background: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. Results: We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in MITF (p.E318K locus, N = 9 cases), BAP1 (N = 3), CDKN2A (N = 2), FLCN (N = 2), and PTEN (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including PIK3CD, NFRKB, EP300, MTOR, and related epigenetic modifier SETD2. The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Conclusions: Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management.
    Keywords:  WES; genetic susceptibility; melanoma; rare variants enrichment; renal cell carcinoma
    DOI:  https://doi.org/10.3390/cancers13092243
  42. BMC Cancer. 2021 Jun 02. 21(1): 662
    Anti-proliferative and pro-apoptotic activity of glycosidic derivatives of lawsone in melanoma cancer cell.
    Mariana Nobre Farias de Franca, Raquel Geralda Isidório, João Henrique Oliveira Bonifacio, Edmilson Willian Propheta Dos Santos, Jileno Ferreira Santos, Flaviano Melo Ottoni, Waldecy de Lucca Junior, Ricardo Scher, Ricardo José Alves, Cristiane Bani Corrêa.
       BACKGROUND: Melanoma is a malignant cancer that affects melanocytes and is considered the most aggressive skin-type cancer. The prevalence for melanoma cancer for the last five year is about one million cases. The impact caused of this and other types of cancer, revel the importance of research into potential active compounds. The natural products are an important source of compounds with biological activity and research with natural products may enable the discovery of compounds with potential activity in tumor cells.
    METHODS: The Sulforhodamine B was used to determine cell density after treatment with lawsone derivatives. Apoptosis and necrosis were analyzed by flow cytometer. Morphological changes were observed by fluorescence using the Phalloidin/FITC and DAPI stains. The clonogenic and wound healing assays were used to analyze reduction of colonies formation and migratory capacity of melanoma cells, respectability.
    RESULTS: In pharmacological screening, seven compounds derived from lawsone were considered to have high cytotoxic activity (GI > 75%). Three compounds were selected to assess the inhibitory concentration for 50% of cells (IC50), and the compound 9, that has IC50 5.3 μM in melanoma cells, was selected for further analyses in this cell line. The clonogenic assay showed that the compound is capable of reducing the formation of melanoma colonies at 10.6 μM concentration. The compound induced apoptotic morphological changes in melanoma cells and increased by 50% the cells dying from apoptosis. Also, this compound reduced the migratory capacity of melanoma cells.
    CONCLUSIONS: The results of this study showed that the evaluated lawsone derivatives have potential activity on tumor cells. The compound 9 is capable of inducing cell death by apoptosis in melanoma cells (B16F10).
    Keywords:  Apoptosis; Clonogenic assay; Cytotoxicity; Flow cytometer; Lawsone; Melanoma; Migration
    DOI:  https://doi.org/10.1186/s12885-021-08404-4
  43. Genes Immun. 2021 Jun 02.
    Early memory differentiation and cell death resistance in T cells predicts melanoma response to sequential anti-CTLA4 and anti-PD1 immunotherapy.
    Isaure Vanmeerbeek, Daniel M Borras, Jenny Sprooten, Oliver Bechter, Sabine Tejpar, Abhishek D Garg.
      Immune checkpoint blockers (ICBs)-based immunotherapy has revolutionised oncology. However, the benefits of ICBs are limited to only a subset of patients. Herein, the biomarkers-driven application of ICBs promises to increase their efficacy. Such biomarkers include lymphocytic IFNγ-signalling and/or cytolytic activity (granzymes and perforin-1) footprints, whose levels in pre-treatment tumours can predict favourable patient survival following ICB-treatment. However, it is not clear whether such biomarkers have the same value in predicting survival of patients receiving first-line anti-CTLA4 ICB-therapy, and subsequently anti-PD1 ICB-therapy (i.e., sequential ICB-immunotherapy regimen). To address this, we applied highly integrated systems/computational immunology approaches to existing melanoma bulk-tumour transcriptomic and single-cell (sc)RNAseq data originating from immuno-oncology clinical studies applying ICB-treatment. Interestingly, we observed that CD8+/CD4+T cell-associated IFNγ-signalling or cytolytic activity signatures fail to predict tumour response in patients treated with anti-CTLA4 ICB-therapy as a first-line and anti-PD1 ICB-therapy in the second-line setting. On the contrary, signatures associated with early memory CD8+/CD4+T cells (integrating TCF1-driven stem-like transcriptional programme), capable of resisting cell death/apoptosis, better predicted objective response rates to ICB-immunotherapy, and favourable survival in the setting of sequential ICB-immunotherapy. These observations suggest that sequencing of ICB-therapy might have a specific impact on the T cell-repertoire and may influence the predictive value of tumoural immune biomarkers.
    DOI:  https://doi.org/10.1038/s41435-021-00138-4
  44. Front Oncol. 2021 ;11 663225
    CRISPR/Cas9 uPAR Gene Knockout Results in Tumor Growth Inhibition, EGFR Downregulation and Induction of Stemness Markers in Melanoma and Colon Carcinoma Cell Lines.
    Alessio Biagioni, Anastasia Chillà, Mario Del Rosso, Gabriella Fibbi, Francesca Scavone, Elena Andreucci, Silvia Peppicelli, Francesca Bianchini, Lido Calorini, Anna Li Santi, Pia Ragno, Francesca Margheri, Anna Laurenzana.
      uPAR is a globular protein, tethered to the cell membrane by a GPI-anchor involved in several cancer-related properties and its overexpression commonly correlates with poor prognosis and metastasis. We investigated the consequences of uPAR irreversible loss in human melanoma and colon cancer cell lines, knocking out its expression by CRISPR/Cas9. We analyzed through flow cytometry, western blotting and qPCR, the modulation of the most known cancer stem cells-associated genes and the EGFR while we observed the proliferation rate exploiting 2D and 3D cellular models. We also generated uPAR "rescue" expression cell lines as well as we promoted the expression of only its 3'UTR to demonstrate the involvement of uPAR mRNA in tumor progression. Knocking out PLAUR, uPAR-encoding gene, we observed an inhibited growth ratio unexpectedly coupled with a significant percentage of cells acquiring a stem-like phenotype. In vivo experiments demonstrated that uPAR loss completely abrogates tumorigenesis despite the gained stem-like profile. Nonetheless, we proved that the reintroduction of the 3'UTR of PLAUR gene was sufficient to restore the wild-type status validating the hypothesis that such a region may act as a "molecular sponge". In particular miR146a, by binding PLAUR 3' UTR region might be responsible for uPAR-dependent inhibition of EGFR expression.
    Keywords:  CRISPR; colon cancer; melanoma; miR146a; urokinase-type plasminogen activator receptor
    DOI:  https://doi.org/10.3389/fonc.2021.663225
  45. Ann Anat. 2021 May 31. pii: S0940-9602(21)00101-1. [Epub ahead of print] 151775
    Choroidal melanocytes: subpopulations of different origin?
    Ludwig M Heindl, Christian Platzl, Heidi Wolfmaier, Martina C Herwig-Carl, Alexandra Kaser-Eichberge, Clemens Strohmaier, Falk Schrödl.
       BACKGROUND: The human choroid derives from the mesectoderm, except the melanocytes originating from the neuroectoderm. To date, it is unclear whether all choroidal melanocytes share the same origin or might have different origins. The purpose of this study was to screen immunohistochemically for mesenchymal elements in the adult healthy human choroid, in the malignant melanoma of the choroid, as well as in the developing human fetal choroid.
    METHODS: Human choroids were obtained from cornea donors and prepared as flat whole mounts for paraffin- and cryoembedding. Globes enucleated for choroidal melanoma and eyes from human fetuses between 11 and 20 weeks of gestation were also embedded in paraffin. Sections were processed for immunohistochemistry of the mesenchymal marker vimentin, the melanocyte marker Melan-A, and the macrophage marker CD68, followed by light-, fluorescence-, and confocal laser scanning-microscopy.
    RESULTS: The normal choroid contained 499 ± 139 vimentin, 384 ± 78 Melan-A, and 129 ± 57 CD68 immunoreactive cells/mm2. The vimentin immunopositive cell density was significantly higher than the density of Melan-A and CD68 immunopositive cells (p < 0.001, respectively). By confocal microscopy, 24 ± 8 % of all choroidal melanocytes displayed vimentin immunoreactivity. In choroidal melanomas, numerous melanoma cells of the epithelioid and spindle cell type revealed immunopositivity for both vimentin and Melan-A. The intratumoral density of vimentin immunoreactive cells was 1758 ± 106 cells/mm2, significantly higher than the density of Melan-A and CD68 immunopositive cells (p < 0.001, respectively). Comparing to healthy choroidal tissue, the choroidal melanomas revealed significantly higher densities of vimentin, Melan-A, and CD68 immunoreactive cells (p < 0.001, respectively). In the developing human fetal choroid, numerous vimentin and Melan-A immunopositive cells were detected not before the 16th week of gestation, with some of them showing colocalization of vimentin and Melan-A.
    CONCLUSIONS: The adult healthy human choroid is endowed with a significant number of vimentin immunopositive mesenchymal structures, including a subpopulation of vimentin immunoreactive choroidal melanocytes. These vimentin immunopositive melanocytic cells are also present in choroidal melanomas as well as in the developing human fetal choroid. Therefore, different embryologic origins can be considered for choroidal melanocytes.
    Keywords:  choroid; embryology; immunohistochemistry; melanocytes; melanoma; vimentin
    DOI:  https://doi.org/10.1016/j.aanat.2021.151775
  46. Artif Cells Nanomed Biotechnol. 2021 Dec;49(1): 461-470
    A polymer-lipid membrane artificial cell nanocarrier containing enzyme-oxygen biotherapeutic inhibits the growth of B16F10 melanoma in 3D culture and in a mouse model.
    Yun Wang, Thomas Ming Swi Chang.
      Melanoma is a deadly skin cancer. Surgery is effective for early stages but there may be remnant cells. Treatments of later stages are associated with severe side effects. Moreover, a dangerous type of melanoma cannot be detected early enough for surgery. There is an urgent need for treatment with less severe side effects. We use a novel system of artificial cell polymer-lipid membrane nanocarrier containing a biomolecular nano-system of enzyme-oxygen biotherapeutic. In this report we show (1) its effectiveness and mechanisms in inhibiting the growth of melanoma in a 3D culture collagen medium that is more similar to that in the animal. (2) This allows us to design and carry out animal studies to successfully show that this can inhibit the growth of melanoma in an animal model. This includes following the tumour sizes and body weights every 2 days for 30 days followed by histology of the sites of injection and vital organs. We also analyze the action of the different components of the nanocarrier-nano-biotherapeutic complex. In conclusion, the results show the safety and clinical feasibility of this approach in the animal model and encourages further study towards clinical use.
    Keywords:  Artificial cells; biomolecular nanosystem; biotherapeutics; drug carriers; nanomedicine; oxygen therapeutics
    DOI:  https://doi.org/10.1080/21691401.2021.1918134
  47. Br J Dermatol. 2021 May 31.
    Melanoma pathology: new approaches and classification.
    I Yeh, B C Bastian.
      Cancer is caused by the accumulation of pathogenic alterations of the genome and epigenome that result in permanent changes that disrupt cellular homeostasis. The genes that become corrupted in this process vary among different tumour types, reflecting specific vulnerabilities and dependencies of the cell from which the cancer originated. This also applies to 'melanoma', a cancer that constitutes not one, but multiple diseases that can be separated based on their cell of origin, aetiology, clinical appearance and course, and response to treatment. In this article, we review the current classification of melanoma within distinct evolutionary pathways and the associated genetic alterations. In addition, we review the application of molecular diagnostics to the diagnosis of melanocytic tumours in the context of histopathological assessment.
    DOI:  https://doi.org/10.1111/bjd.20427
  48. Cancers (Basel). 2021 May 21. pii: 2529. [Epub ahead of print]13(11):
    Real-World Experience with Targeted Therapy in BRAF Mutant Advanced Melanoma Patients: Results from a Multicenter Retrospective Observational Study Advanced Melanoma in Russia (Experience) (ADMIRE).
    Kristina V Orlova, Evgeniy V Ledin, Natalia V Zhukova, Rashida V Orlova, Elena V Karabina, Mikhail V Volkonskiy, Daniil L Stroyakovskiy, Aleksandr N Yurchenkov, Svetlana A Protsenko, Alexey V Novik, Ludmila V Vorotilina, Fedor V Moiseenko, Victor L Chang, Aleksandr I Kazmin, Svetlana A Tkachenko, Sergey V Gamaunov, David R Naskhletashvili, Igor V Samoylenko, Anastasia S Vikhrova, Igor A Utyashev, Galina Yu Kharkevich, Natalia N Petenko, Irina Zh Shubina, Lev V Demidov.
      Clinical trials of targeted therapy (TT) and immunotherapy (IT) for highly aggressive advanced melanoma have shown marked improvements in response and survival rates. However, real-world data on treatment patterns and clinical outcomes for patients with advanced BRAF V600 mutant melanoma are ultimately scarce. The study was designed as an observational retrospective chart review study, which included 382 patients with advanced BRAF V600 mutant melanoma, who received TT in a real-world setting and were not involved in clinical trials. The data were collected from twelve medical centers in Russia. The objective response rates (ORRs) to combined BRAFi plus MEKi and to BRAFi mono-therapy were 57.4% and 39.8%, respectively. The median progression-free survival (PFS) and median overall survival (OS) were 9.2 months and 22.6 months, respectively, for the combined first-line therapy; 9.4 months and 16.1 months, respectively, for the combined second-line therapy; and 7.4 months and 17.1 months, respectively, for the combined third- or higher-line therapy. Analysis of treatment patterns demonstrated the effectiveness of the combined TT with BRAF plus MEK inhibitors in patients with brain metastases, rare types of BRAF mutations, and across lines of therapy, as well as a well-tolerated and manageable safety profile.
    Keywords:  BRAF; MEK; chart review; cobimetinib; dabrafenib; melanoma; trametinib; vemurafenib
    DOI:  https://doi.org/10.3390/cancers13112529
  49. Cell Syst. 2021 May 27. pii: S2405-4712(21)00158-7. [Epub ahead of print]
    Interpretable deep learning uncovers cellular properties in label-free live cell images that are predictive of highly metastatic melanoma.
    Assaf Zaritsky, Andrew R Jamieson, Erik S Welf, Andres Nevarez, Justin Cillay, Ugur Eskiocak, Brandi L Cantarel, Gaudenz Danuser.
      Deep learning has emerged as the technique of choice for identifying hidden patterns in cell imaging data but is often criticized as "black box." Here, we employ a generative neural network in combination with supervised machine learning to classify patient-derived melanoma xenografts as "efficient" or "inefficient" metastatic, validate predictions regarding melanoma cell lines with unknown metastatic efficiency in mouse xenografts, and use the network to generate in silico cell images that amplify the critical predictive cell properties. These exaggerated images unveiled pseudopodial extensions and increased light scattering as hallmark properties of metastatic cells. We validated this interpretation using live cells spontaneously transitioning between states indicative of low and high metastatic efficiency. This study illustrates how the application of artificial intelligence can support the identification of cellular properties that are predictive of complex phenotypes and integrated cell functions but are too subtle to be identified in the raw imagery by a human expert. A record of this paper's transparent peer review process is included in the supplemental information. VIDEO ABSTRACT.
    Keywords:  interpretable deep learning; live cell imaging; melanoma metastasis
    DOI:  https://doi.org/10.1016/j.cels.2021.05.003
  50. Clin Exp Dermatol. 2021 Jun 03.
    Melanoma and eruptive nevi during cetuximab treatment: EGFR inhibitors and a common concern.
    T Ferrari, M Lambertini, F Tartari, E Dika.
      A 59-year-old patient was referred to the Melanoma Unit for a dermatologic consultation due to the eruptive onset of multiple hyperpigmented nevi one-month after the beginning of their medical therapy with cetuximab for metastatic colorectal cancer. No other side-effects were reported, with the exception of a mild cutaneous xerosis.
    DOI:  https://doi.org/10.1111/ced.14787
  51. Int J Environ Res Public Health. 2021 May 20. pii: 5479. [Epub ahead of print]18(10):
    Skin Cancer Detection: A Review Using Deep Learning Techniques.
    Mehwish Dildar, Shumaila Akram, Muhammad Irfan, Hikmat Ullah Khan, Muhammad Ramzan, Abdur Rehman Mahmood, Soliman Ayed Alsaiari, Abdul Hakeem M Saeed, Mohammed Olaythah Alraddadi, Mater Hussen Mahnashi.
      Skin cancer is one of the most dangerous forms of cancer. Skin cancer is caused by un-repaired deoxyribonucleic acid (DNA) in skin cells, which generate genetic defects or mutations on the skin. Skin cancer tends to gradually spread over other body parts, so it is more curable in initial stages, which is why it is best detected at early stages. The increasing rate of skin cancer cases, high mortality rate, and expensive medical treatment require that its symptoms be diagnosed early. Considering the seriousness of these issues, researchers have developed various early detection techniques for skin cancer. Lesion parameters such as symmetry, color, size, shape, etc. are used to detect skin cancer and to distinguish benign skin cancer from melanoma. This paper presents a detailed systematic review of deep learning techniques for the early detection of skin cancer. Research papers published in well-reputed journals, relevant to the topic of skin cancer diagnosis, were analyzed. Research findings are presented in tools, graphs, tables, techniques, and frameworks for better understanding.
    Keywords:  deep learning; deep neural network (DNN); machine learning; melanoma; skin lesion; support vector machine (SVM)
    DOI:  https://doi.org/10.3390/ijerph18105479
  52. Pigment Cell Melanoma Res. 2021 May 31.
    A Novel BLOC1S5-Related HPS-11 Patient and Zebrafish with bloc1s5 Disruption.
    Zilin Zhong, Zhuanbin Wu, Jun Zhang, Jianjun Chen.
      HPS (Hermansky-Pudlak Syndrome) cases present with a variable degree of OCA and bleeding tendency. HPS is categorized into eleven types based on eleven causative genes and disease severity varies among different types. By whole exome sequencing performed on a family trio and Sanger sequencing of candidate variants, we identified a novel homozygous variant (NM_201280.3: c.181delC, p.Val61*) in BLOC1S5 in the patient who presents OCA and mild bleeding diathesis, and his healthy parents are heterozygous carriers. The variant can be considered pathogenic based on the guideline American College of Medical Genetics and Genomics and the patient is proposed to be affected with HPS-11. In this study, we also explored bloc1s5 in zebrafish. bloc1s5 mRNA can be detected during early development of zebrafish. bloc1s5 knockdown zebrafish present with retinal hypopigmentation, thrombocytes loss and pericardial oedema, and dll4/notch1 signaling and vascular integrity signaling are downregulated at mRNA level in bloc1s5 morphants. The data from the first HPS-11 patient in Chinese population expands phenotypic and genotypic spectrum of HPS-11. Disruption of bloc1s5 in zebrafish recapitulates HPS-11-like phenotypes and the potential signaling pathways associated with bloc1s5 are proposed. Altogether, this study may facilitate genetic counseling of HPS and investigation about BLOC1S5.
    Keywords:   BLOC1S5 ; HPS-11; Hermansky-Pudlak Syndrome; Oculocutaneous albinism; bleeding tendency; hypopigmentation; zebrafish
    DOI:  https://doi.org/10.1111/pcmr.12995
  53. Cells. 2021 May 25. pii: 1310. [Epub ahead of print]10(6):
    Fucosylated Proteome Profiling Identifies a Fucosylated, Non-Ribosomal, Stress-Responsive Species of Ribosomal Protein S3.
    Gregory Watson, Daniel Lester, Hui Ren, Connor M Forsyth, Elliot Medina, David Gonzalez Perez, Lancia Darville, Jiqiang Yao, Vince Luca, John Koomen, Ling Cen, Eric Lau.
      Alterations in genes encoding for proteins that control fucosylation are known to play causative roles in several developmental disorders, such as Dowling-Degos disease 2 and congenital disorder of glycosylation type IIc (CDGIIc). Recent studies have provided evidence that changes in fucosylation can contribute to the development and progression of several different types of cancers. It is therefore important to gain a detailed understanding of how fucosylation is altered in disease states so that interventions may be developed for therapeutic purposes. In this report, we find that fucosylation occurs on many intracellular proteins. This is an interesting finding, as the fucosylation machinery is restricted to the secretory pathway and is thought to predominately affect cell-membrane-bound and secreted proteins. We find that Ribosomal protein S3 (RPS3) is fucosylated in normal tissues and in cancer cells, and that the extent of its fucosylation appears to respond to stress, including MAPK inhibitors, suggesting a new role in posttranslational protein function. Our data identify a new ribosome-independent species of fucosylated RPS3 that interacts with proteins involved in posttranscriptional regulation of RNA, such as Heterogeneous nuclear ribonucleoprotein U (HNRNPU), as well as with a predominance of non-coding RNAs. These data highlight a novel role for RPS3, which, given previously reported oncogenic roles for RPS3, might represent functions that are perturbed in pathologies such as cancer. Together, our findings suggest a previously unrecognized role for fucosylation in directly influencing intracellular protein functions.
    Keywords:  fucosylation; melanoma; ribosomal protein S3
    DOI:  https://doi.org/10.3390/cells10061310
  54. Int J Dermatol. 2021 May 26.
    Accuracy of clinical-dermatoscopic versus dermatopathologic diagnosis of melanoma and non-melanoma skin cancer.
    Cláudio de Lélis Filgueiras de Souza, Guilherme Gonçalves Nascimento, João Paulo de Oliveira, Júlia Carvalho Giannini, Roberta Bessa de Veloso Silva, Adilson da Costa.
      
    DOI:  https://doi.org/10.1111/ijd.15674
  55. Cancers (Basel). 2021 May 14. pii: 2372. [Epub ahead of print]13(10):
    Afucosylated IgG Targets FcγRIV for Enhanced Tumor Therapy in Mice.
    Rens Braster, Marijn Bögels, Hreinn Benonisson, Manfred Wuhrer, Rosina Plomp, Arthur E H Bentlage, Rianne Korthouwer, Remco Visser, J Sjef Verbeek, Marjolein van Egmond, Gestur Vidarsson.
      Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (FcγR) IIIa/b, resulting in enhanced antibody dependent cell cytotoxicity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We generated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine FcγRIV, the mouse orthologue of human FcγRIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in FcγRIV-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies.
    Keywords:  Fc-receptors; afucosylated IgG; melanoma
    DOI:  https://doi.org/10.3390/cancers13102372
  56. J Am Acad Dermatol. 2021 May 27. pii: S0190-9622(21)01012-4. [Epub ahead of print]
    Increased melanoma recurrence in patients with multiple primary invasive melanomas.
    Adele C Green, Maria Celia B Hughes, Gail M Williams, Maryrose Malt, Vanessa L Beesley, Kiarash Khosrotehrani, B Mark Smithers.
      
    DOI:  https://doi.org/10.1016/j.jaad.2021.05.025
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