@article{HelmprobstKneitzKlotzetal.2021, author = {Helmprobst, Frederik and Kneitz, Susanne and Klotz, Barbara and Naville, Magali and Dechaud, Corentin and Volff, Jean-Nicolas and Schartl, Manfred}, title = {Differential expression of transposable elements in the medaka melanoma model}, series = {PLoS One}, volume = {16}, journal = {PLoS One}, number = {10}, doi = {10.1371/journal.pone.0251713}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260615}, year = {2021}, abstract = {Malignant melanoma incidence is rising worldwide. Its treatment in an advanced state is difficult, and the prognosis of this severe disease is still very poor. One major source of these difficulties is the high rate of metastasis and increased genomic instability leading to a high mutation rate and the development of resistance against therapeutic approaches. Here we investigate as one source of genomic instability the contribution of activation of transposable elements (TEs) within the tumor. We used the well-established medaka melanoma model and RNA-sequencing to investigate the differential expression of TEs in wildtype and transgenic fish carrying melanoma. We constructed a medaka-specific TE sequence library and identified TE sequences that were specifically upregulated in tumors. Validation by qRT- PCR confirmed a specific upregulation of a LINE and an LTR element in malignant melanomas of transgenic fish.}, language = {en} } @article{AnelliOrdasKneitzetal.2018, author = {Anelli, Viviana and Ordas, Anita and Kneitz, Susanne and Sagredo, Leonel Munoz and Gourain, Victor and Schartl, Manfred and Meijer, Annemarie H. and Mione, Marina}, title = {Ras-Induced miR-146a and 193a Target Jmjd6 to Regulate Melanoma Progression}, series = {Frontiers in Genetics}, volume = {9}, journal = {Frontiers in Genetics}, number = {675}, issn = {1664-8021}, doi = {10.3389/fgene.2018.00675}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196963}, year = {2018}, abstract = {Ras genes are among the most commonly mutated genes in human cancer; yet our understanding of their oncogenic activity at the molecular mechanistic level is incomplete. To identify downstream events that mediate ras-induced cellular transformation in vivo, we analyzed global microRNA expression in three different models of Ras-induction and tumor formation in zebrafish. Six microRNAs were found increased in Ras-induced melanoma, glioma and in an inducible model of ubiquitous Ras expression. The upregulation of the microRNAs depended on the activation of the ERK and AKT pathways and to a lesser extent, on mTOR signaling. Two Ras-induced microRNAs (miR-146a and 193a) target Jmjd6, inducing downregulation of its mRNA and protein levels at the onset of Ras expression during melanoma development. However, at later stages of melanoma progression, jmjd6 levels were found elevated. The dynamic of Jmjd6 levels during progression of melanoma in the zebrafish model suggests that upregulation of the microRNAs targeting Jmjd6 may be part of an anti-cancer response. Indeed, triple transgenic fish engineered to express a microRNA-resistant Jmjd6 from the onset of melanoma have increased tumor burden, higher infiltration of leukocytes and shorter melanoma-free survival. Increased JMJD6 expression is found in several human cancers, including melanoma, suggesting that the up-regulation of Jmjd6 is a critical event in tumor progression. The following link has been created to allow review of record GSE37015: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jjcrbiuicyyqgpc\&acc=GSE37015.}, language = {en} } @article{GrimmHufnagelWobseretal.2018, author = {Grimm, Johannes and Hufnagel, Anita and Wobser, Marion and Borst, Andreas and Haferkamp, Sebastian and Houben, Roland and Meierjohann, Svenja}, title = {BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1}, series = {Oncogenesis}, volume = {7}, journal = {Oncogenesis}, number = {71}, doi = {10.1038/s41389-018-0082-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177261}, year = {2018}, abstract = {Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.}, language = {en} } @article{KneitzMishraChalopinetal.2016, author = {Kneitz, Susanne and Mishra, Rasmi R. and Chalopin, Domitille and Postlethwait, John and Warren, Wesley C. and Walther, Ronald B. and Schartl, Manfred}, title = {Germ cell and tumor associated piRNAs in the medaka and \(Xiphophorus\) melanoma models}, series = {BMC Genomics}, volume = {17}, journal = {BMC Genomics}, number = {357}, doi = {10.1186/s12864-016-2697-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146028}, year = {2016}, abstract = {Background A growing number of studies report an abnormal expression of Piwi-interacting RNAs (piRNAs) and the piRNA processing enzyme Piwi in many cancers. Whether this finding is an epiphenomenon of the chaotic molecular biology of the fast dividing, neoplastically transformed cells or is functionally relevant to tumorigenesisis is difficult to discern at present. To better understand the role of piRNAs in cancer development small laboratory fish models can make a valuable contribution. However, little is known about piRNAs in somatic and neoplastic tissues of fish. Results To identify piRNA clusters that might be involved in melanoma pathogenesis, we use several transgenic lines of medaka, and platyfish/swordtail hybrids, which develop various types of melanoma. In these tumors Piwi, is expressed at different levels, depending on tumor type. To quantify piRNA levels, whole piRNA populations of testes and melanomas of different histotypes were sequenced. Because no reference piRNA cluster set for medaka or Xiphophorus was yet available we developed a software pipeline to detect piRNA clusters in our samples and clusters were selected that were enriched in one or more samples. We found several loci to be overexpressed or down-regulated in different melanoma subtypes as compared to hyperpigmented skin. Furthermore, cluster analysis revealed a clear distinction between testes, low-grade and high-grade malignant melanoma in medaka. Conclusions Our data imply that dysregulation of piRNA expression may be associated with development of melanoma. Our results also reinforce the importance of fish as a suitable model system to study the role of piRNAs in tumorigenesis.}, language = {en} } @article{TomeiAdamsUccellinietal.2012, author = {Tomei, Sara and Adams, Sharon and Uccellini, Lorenzo and Bedognetti, Davide and De Giorgi, Valeria and Erdenebileg, Narnygerel and Libera Ascierto, Maria and Reinboth, Jennifer and Liu, Qiuzhen and Bevilacqua, Generoso and Wang, Ena and Mazzanti, Chiara and Marincola, Francesco M.}, title = {Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population}, series = {Medical Oncology}, volume = {29}, journal = {Medical Oncology}, number = {5}, doi = {dx.doi.org/10.1007/s12032-012-0255-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126834}, pages = {3456-3461}, year = {2012}, abstract = {HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case-control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.}, language = {en} } @article{HaydnHufnagelGrimmetal.2014, author = {Haydn, Johannes M. and Hufnagel, Anita and Grimm, Johannes and Maurus, Katja and Schartl, Manfred and Meierjohann, Svenja}, title = {The MAPK pathway as an apoptosis enhancer in melanoma}, series = {Oncotarget}, volume = {5}, journal = {Oncotarget}, number = {13}, issn = {1949-2553}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120649}, pages = {5040-53}, year = {2014}, abstract = {Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAFV600E-mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAFV600E-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.}, language = {en} } @article{Meierjohann2015, author = {Meierjohann, Svenja}, title = {Hypoxia independent drivers of melanoma angiogenesis}, series = {Frontiers in Oncology}, volume = {5}, journal = {Frontiers in Oncology}, number = {120}, doi = {10.3389/fonc.2015.00102}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125586}, year = {2015}, abstract = {Tumor angiogenesis is a process which is traditionally regarded as the tumor's response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a pre-requisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia-independent mechanisms of tumor angiogenesis in melanoma.}, language = {en} } @article{WittbrodtLammersMalitscheketal.1992, author = {Wittbrodt, Joachim and Lammers, Reiner and Malitschek, Barbara and Ullrich, Axel and Schartl, Manfred}, title = {Xmrk receptor tyrosine kinase is activated in Xiphophorus malignant melanoma}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61699}, year = {1992}, abstract = {Xmrk encodes a putative transmembrane glycoprotein of the tyrosine kinase family and is a melanoma-inducing gene in Xiphophorus. We attempted to investigate the biological function of the putative Xmrk receptor by characterizing its signalling properties. Since a potential Iigand for Xmrk has not yet been identified, it has been difficult to analyse the biochemical properlies and biological function of this cell surface protein. In an approach towards such analyses, the Xmrk extracellular domain was replaced by the closely related Iigand-binding domain sequences of the human epidennal growth factor receptor (HER) and the ligand-induced activity of the chimeric HER-Xmrk proteinwas examined. We show that the Xmrk protein is a functional receptor tyrosine kinase, is highly active in malignant melanoma and displays a constitutive autophosphorylation activity possibly due to an activating mutation in its extracellular or transmembrane domain. In the focus formation assay the HER-Xmrk chimera is a potent transfonning protein equivalent to other tyrosine kinase oncoproteins.}, subject = {Physiologische Chemie}, language = {en} }