TY - JOUR A1 - Elkon, Ran A1 - Loayza-Puch, Fabricio A1 - Korkmaz, Gozde A1 - Lopes, Rui A1 - van Breugel, Pieter C A1 - Bleijerveld, Onno B A1 - Altelaar, AF Maarten A1 - Wolf, Elmar A1 - Lorenzin, Francesca A1 - Eilers, Martin A1 - Agami, Reuven T1 - Myc coordinates transcription and translation to enhance transformation and suppress invasiveness JF - EMBO reports N2 - c‐Myc is one of the major human proto‐oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc‐induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript‐specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFβ pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc‐induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells. KW - c‐Myc KW - transcriptional responses KW - translational regulation KW - transcription KW - transformation KW - metastasis KW - cancer KW - protein biosynthesis & quality control Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150373 VL - 16 IS - 12 ER - TY - JOUR A1 - Leikam, C A1 - Hufnagel, AL A1 - Otto, C A1 - Murphy, DJ A1 - Mühling, B A1 - Kneitz, S A1 - Nanda, I A1 - Schmid, M A1 - Wagner, TU A1 - Haferkamp, S A1 - Bröcker, E-B A1 - Schartl, M A1 - Meierjohann, S T1 - In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells JF - Cell Death and Disease N2 - Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi-or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS\(^{61K}\) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation. KW - reactive oxygen KW - human melanoma KW - MITF KW - cancer KW - skin KW - DNA damage KW - kappa-B KW - oncogene-induced senescence KW - cellular senescence Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148718 VL - 6 IS - e1711 ER - TY - JOUR A1 - Schartl, Manfred A1 - Shen, Yingjia A1 - Maurus, Katja A1 - Walter, Ron A1 - Tomlinson, Chad A1 - Wilson, Richard K. A1 - Postlethwait, John A1 - Warren, Wesley C. T1 - Whole body melanoma transcriptome response in medaka JF - PLoS ONE N2 - The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model. KW - metastatic melanoma KW - expression KW - fish KW - cancer KW - stage III KW - melanogenesis KW - genome cells KW - gene KW - contributes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144714 VL - 10 IS - 12 ER -