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In the vertebrate retina, several dozens of parallel channels relay information about the visual world to the brain. These channels are represented by the different types of retinal ganglion cells (RGCs), whose responses are rendered selective for distinct sets of visual features by various mechanisms. These mechanisms can be roughly grouped into synaptic interactions and cell-intrinsic mechanisms, with the latter including dendritic morphology as well as ion channel complement and distribution. Here, we investigate how strongly ion channel complement can shape RGC output by comparing two mouse RGC types, the well-described ON alpha cell and a little-studied ON cell that is EGFP-labelled in the Igfbp5 mouse line and displays an unusual selectivity for stimuli with high contrast. Using patch-clamp recordings and computational modelling, we show that a higher activation threshold and a pronounced slow inactivation of the voltage-gated Na+ channels contribute to the distinct contrast tuning and transient responses in ON Igfbp5 RGCs, respectively. In contrast, such a mechanism could not be observed in ON alpha cells. This study provides an example for the powerful role that the last stage of retinal processing can play in shaping RGC responses. [ABSTRACT FROM AUTHOR]

Melanoma is the deadliest form of skin cancer showing rising incidence over the past years. New insights into the mechanisms of melanoma progression contributed to the development of novel treatment options, such as immunotherapies. However, acquiring resistance to treatment poses a big problem to therapy success. Therefore, understanding the mechanisms underlying resistance could improve therapy efficacy. Correlating expression levels in tissue samples of primary melanoma and metastases revealed that secretogranin 2 (SCG2) is highly expressed in advanced melanoma patients with poor overall survival (OS) rates. By conducting transcriptional analysis between SCG2-overexpressing (OE) and control melanoma cells, we detected a downregulation of components of the antigen presenting machinery (APM), which is important for the assembly of the MHC class I complex. Flow cytometry analysis revealed a downregulation of surface MHC class I expression on melanoma cells that showed resistance towards the cytotoxic activity of melanoma-specific T cells. IFNγ treatment partially reversed these effects. Based on our findings, we suggest that SCG2 might stimulate mechanisms of immune evasion and therefore be associated with resistance to checkpoint blockade and adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

Developmental Dyslexia (DD) is a life-long deficit in reading and spelling with unclear causes. DD negatively impacts many language skills. Relatively little is known about whether skills of pragmatic competence are compromised in individuals with DD. Here, we assess DD symptomatology in a group of native German dyslexic adults. We first test for the presence of DD subtypes along the dimensions of phonological awareness and naming speed, two key deficits in DD. We then assess pragmatic competence in adults with DD compared to control participants without DD. We found that a subclassification of DD according to phonological awareness and naming speed only partially applies and that dyslexic participants show a lower pragmatic competence than control participants. [ABSTRACT FROM AUTHOR]

Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment. [Display omitted] • Aging promotes a decline in CD9 expression in dermal fibroblast extracellular vesicles • Loss of CD9 drives secretion of the angiogenesis promotor ANGPTL2 in extracellular vesicles • Extracellular vesicles increase angiogenesis in melanoma in an age-dependent manner Hüser et al. show that an age-associated decline in CD9 expression in dermal fibroblasts promotes the secretion of CD9-low and ANGPTL2-high extracellular vesicles. The loss of CD9 promotes angiogenesis and presents an age-related mechanism, which could drive melanoma progression. [ABSTRACT FROM AUTHOR]

Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAFV600E‐mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi‐resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma. What's new? In melanoma therapy, resistance to targeted therapeutics such as vemurafenib has emerged as a serious clinical problem. In this study, the authors found that increased expression of an oncogenic transcription factor called 'FOXD1' correlates with a poor prognosis in melanoma patients. They also found that FOXD1 promotes targeted‐therapy resistance in human melanoma cells, by upregulating the expression of the CTGF oncogene. These results indicate that FOXD1 may represent a novel therapeutic target in certain treatment‐resistant melanomas, as well as a useful prognostic biomarker. [ABSTRACT FROM AUTHOR]

CD24 is a highly glycosylated protein with a small protein core that is linked to the plasma membrane via a glycosyl‐phosphatidylinositol anchor. CD24 is primarily expressed by immune cells but is often overexpressed in human tumors. In cancer, CD24 is a regulator of cell migration, invasion and proliferation. Its expression is associated with poor prognosis and it is used as cancer stemness marker. Recently, CD24 on tumor cells was identified as a phagocytic inhibitor ("do not eat me" signal) having a suppressive role in tumor immunity via binding to Siglec‐10 on macrophages. This finding is reminiscent of the demonstration that soluble CD24‐Fc can dampen the immune system in autoimmune disease. In the present review, we summarize recent progress on the role of the CD24‐Siglec‐10 binding axis at the interface between tumor cells and the immune system, and the role of CD24 genetic polymorphisms in cancer. We describe the specific function of cytoplasmic CD24 and discuss the presence of CD24 on tumor‐released extracellular vesicles. Finally, we evaluate the potential of CD24‐based immunotherapy. [ABSTRACT FROM AUTHOR]

Alterations in histone modifications play a crucial role in the progression of various types of cancer. The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9. Here, we describe how overexpression of SETDB1 contributes to melanoma tumorigenesis. SETDB1 is highly amplified in melanoma cells and in the patient tumors. Increased expression of SETDB1, which correlates with SETDB1 amplification, is associated with a more aggressive phenotype in in vitro and in vivo studies. Mechanistically, SETDB1 implements its effects via regulation of thrombospondin 1, and the SET‐domain of SETDB1 is essential for the maintenance of its tumorigenic activity. Inhibition of SETDB1 reduces cell growth in melanomas resistant to targeted treatments. Our results indicate that SETDB1 is a major driver of melanoma development and may serve as a potential future target for the treatment of this disease. What's new? Alterations in histone modifications play a crucial role in the progression of various types of cancer. The histone methyltransferase SETDB1 is known to be involved in malignant melanoma. However, little is known about its effects or mechanisms of action in humans. In this study, the authors found that increased SETDB1 expression is linked to poor prognosis in melanoma patients, and that SETDB1 regulates expression of the oncogene THBS1. They also found that inhibiting SETDB1 leads to a strong reduction in melanoma‐cell viability. This enzyme may thus offer a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Melanoma is often characterized by a constitutively active RAS‐RAF‐MEK‐ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy‐resistant, melanoma‐derived induced pluripotent cancer cells (iPCCs). SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell‐like phenotype associated with resistance. We, therefore, elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that the upregulation of SOX2 and CD24 required activation of STAT3 and that SOX2 induced the expression of CD24 by binding to its promoter. We find that the overexpression of SOX2 or CD24 significantly increases the resistance toward BRAF inhibitors, while SOX2 knock‐down rendered cells more sensitivity toward treatment. The overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, by either CD24 knock‐down or Src/STAT3 inhibition in resistant SOX2‐overexpressing cells, the sensitivity toward BRAF inhibitors was re‐established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the activation of STAT3, SOX2 and CD24. Thus, to prevent adaptive resistance, it might be beneficial to combine Src/STAT3 inhibitors together with MAPK pathway inhibitors. What's new? While BRAF inhibitors are established in melanoma treatment, resistance developed during ongoing therapy and adaptive resistance, which emerges immediately upon treatment, are problematic. Here, in melanoma induced‐pluripotent cancer cells, BRAF inhibitor treatment was found to contribute to early STAT3 activation and SOX2 upregulation, with a subsequent increase in CD24 expression. Following SOX2 or CD24 overexpression, Src and STAT3 activity and adaptive resistance also increased. SOX2 or CD24 knockdown, by contrast, rendered cells sensitive to BRAF inhibition. This mechanism, whereby tumor cells circumvent BRAF inhibitory effects via STAT3, SOX2 and CD24 activation, likely underlies adaptive resistance to BRAF inhibitors in melanoma. [ABSTRACT FROM AUTHOR]

The sry-related high-mobility box ( SOX)-2 protein has recently been proven to play a significant role in progression, metastasis, and clinical prognosis spanning several cancer types. Research on the role of SOX2 in melanoma is limited and currently little is known about the mechanistic function of this gene in this context. Here, we observed high expression of SOX2 in both human melanoma cell lines and primary melanomas in contrast to melanocytic nevi. This overexpression in melanoma can, in part, be explained by extra gene copy numbers of SOX2 in primary samples. Interestingly, we were able to induce SOX2 expression, mediated by SOX4, via TGF- β1 stimulation in a time-dependent manner. Moreover, the knockdown of SOX2 impaired TGF- β-induced invasiveness. This phenotype switch can be explained by SOX2-mediated cross talk between TGF- β and non-canonical Wnt signaling. Thus, we propose that SOX2 is involved in the critical TGF- β signaling pathway, which has been shown to correlate with melanoma aggressiveness and metastasis. In conclusion, we have identified a novel downstream factor of TGF- β signaling in melanoma, which may have further implications in the clinic. [ABSTRACT FROM AUTHOR]

Eye formation in vertebrates is controlled by a conserved pattern of molecular networks. Homeobox transcription factors are crucially involved in the establishment and maintenance of the retina. A previous study of Massé et al. (Nature, 449: 1058-62, 2007) using morpholino knockdown identified the ectonucleotidase NTPDase2 and the P2Y receptor as essential elements for eye formation in embryos of the clawed frog Xenopus laevis. In order to investigate whether a similarly essential mechanism would be active in mammalian eye development, we analyzed mice KO for Entpd2 or P2ry1 as well as double KO for Entpd2/ P2ry1. These mice developed normal eyes. In order to identify potential deficits in the molecular identity or in the arrangement of the cellular elements of the retina, we performed an immunohistological analysis using a variety of retinal markers. The analysis of single and double KO mice demonstrated that NTPDase2 and P2Y receptors are not required for murine eye formation, as previously shown for eye development in Xenopus laevis. [ABSTRACT FROM AUTHOR]

Simple Summary: The major obstacle for the long-term success of targeted therapies in melanoma is the occurrence of resistance. Here, we present a new mechanism of targeted therapy resistance in melanoma where the treatment with the BRAF inhibitor vemurafenib causes an increased activation of HER3 via shed ligands. This is followed by an activation of STAT3 via HER3 and results in the expression of the STAT3 target gene SOX2. Pharmacological inhibition of HERs sensitizes melanoma cells toward vemurafenib treatment. Thus, blocking HER family members and especially HER3 in addition to targeted therapy treatment might prevent the occurrence of resistance. Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 (SOX2) and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies. [ABSTRACT FROM AUTHOR]

The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate human melanoblasts: (1) via differentiation from induced pluripotent stem cells (iPSCs) and (2) via dedifferentiation from melanocytes. The melanoblast transcriptomes were then compared to the transcriptome of MAPK inhibitor-resistant melanoma cells. We observed that the expression of genes associated with cell cycle control, DNA damage control, metabolism, and cancer was altered in both melanoblast populations and in both adaptive and acquired resistant melanoma samples, compared to drug-sensitive samples. However, genes involved in antigen presentation and cellular movement were only regulated in the melanoblast populations and in the acquired resistant melanoma samples, compared to the drug-sensitive samples. Moreover, melanocyte-derived melanoblasts and adaptive resistant melanoma samples were characterized by different expression levels of certain transcription factors or genes involved in the CDK5 pathway. In conclusion, we show here that in vitro models of human melanoblasts are very important tools to comprehend the expression profiles of drug-resistant melanoma. [ABSTRACT FROM AUTHOR]