EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice.

Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.

[1]  I. Vargel,et al.  Clear cell sarcoma , 2014, Indian dermatology online journal.

[2]  U. Suter,et al.  Schwann Cell Precursors from Nerve Innervation Are a Cellular Origin of Melanocytes in Skin , 2009, Cell.

[3]  K. Shimizu,et al.  Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma , 2009, Journal of Cancer Research and Clinical Oncology.

[4]  L. Michel,et al.  c-Fos overexpression increases the proliferation of human hepatocytes by stabilizing nuclear Cyclin D1. , 2008, World journal of gastroenterology.

[5]  Malay Haldar,et al.  A conditional mouse model of synovial sarcoma: insights into a myogenic origin. , 2007, Cancer cell.

[6]  D. Fisher,et al.  MITF: master regulator of melanocyte development and melanoma oncogene. , 2006, Trends in molecular medicine.

[7]  C. Denny,et al.  Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. , 2006, Cancer cell.

[8]  Rudolf Jaenisch,et al.  Efficient method to generate single‐copy transgenic mice by site‐specific integration in embryonic stem cells , 2006, Genesis.

[9]  A. Trumpp,et al.  Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells. , 2005, Cancer research.

[10]  Y. Banno,et al.  Inhibition of Platelet-derived Growth Factor-induced Cell Growth Signaling by a Short Interfering RNA for EWS-Fli1 via Down-regulation of Phospholipase D2 in Ewing Sarcoma Cells* , 2005, Journal of Biological Chemistry.

[11]  T. Golub,et al.  Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma , 2005, Nature.

[12]  Rudolf Jaenisch,et al.  Ectopic Expression of Oct-4 Blocks Progenitor-Cell Differentiation and Causes Dysplasia in Epithelial Tissues , 2005, Cell.

[13]  K. Schaefer,et al.  The melanocyte inducing factor MITF is stably expressed in cell lines from human clear cell sarcoma , 2003, British Journal of Cancer.

[14]  William Stafford Noble,et al.  Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Takuro Nakamura,et al.  Identification of target genes for EWS/ATF-1 chimeric transcription factor , 2003, Oncogene.

[16]  I. Weinstein.  Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[17]  A. Ferrari,et al.  Clear cell sarcoma of tendons and aponeuroses in pediatric patients , 2002, Cancer.

[18]  Y. Maehara,et al.  Newly established clear cell sarcoma (malignant melanoma of soft parts) cell line expressing melanoma-associated Melan-A antigen and overexpressing C-MYC oncogene. , 2002, Cancer genetics and cytogenetics.

[19]  M. Ladanyi,et al.  Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases. , 2002, The Journal of molecular diagnostics : JMD.

[20]  A. Sandberg,et al.  Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell sarcoma (malignant melanoma of soft parts). , 2001, Cancer genetics and cytogenetics.

[21]  J. W. Finley,et al.  Clear cell sarcoma: The Roswell Park experience , 2001, Journal of surgical oncology.

[22]  Shankar Srinivas,et al.  Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus , 2001, BMC Developmental Biology.

[23]  A. McMahon,et al.  Fate of the mammalian cardiac neural crest. , 2000, Development.

[24]  A. McMahon,et al.  Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. , 2000, Development.

[25]  C. R. Pinkerton,et al.  Clear cell sarcoma. , 1999, Pediatric hematology and oncology.

[26]  J. Peterse,et al.  Clear cell sarcoma (malignant melanoma) of soft parts , 1999, Cancer.

[27]  K. Abe,et al.  A novel transgenic technique that allows specific marking of the neural crest cell lineage in mice. , 1999, Developmental biology.

[28]  Erica A Golemis,et al.  Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II , 1998, Oncogene.

[29]  S. Pan,et al.  The EWS/ATF1 fusion protein contains a dispersed activation domain that functions directly , 1998, Oncogene.

[30]  Kevin A. W. Lee,et al.  MMSP tumor cells expressing the EWS/ATF1 oncogene do not support cAMP-inducible transcription , 1998, Oncogene.

[31]  J. Pelletier,et al.  The DNA binding domains of the WT1 tumor suppressor gene product and chimeric EWS/WT1 oncoprotein are functionally distinct , 1998, Oncogene.

[32]  O. Seternes,et al.  Synergistic increase in c-fos expression by simultaneous activation of the ras/raf/map kinase- and protein kinase A signaling pathways is mediated by the c-fos AP-1 and SRE sites. , 1998, Biochimica et biophysica acta.

[33]  J. Miyazaki,et al.  A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. , 1997, Biochemical and biophysical research communications.

[34]  E. van Marck,et al.  Malignant melanoma of the soft parts (clear-cell sarcoma): confirmation of EWS and ATF-1 gene fusion caused by a t(12;22) translocation. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[35]  L. Lee,et al.  The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator. , 1996, Oncogene.

[36]  B. Spiegelman,et al.  c-fos is required for malignant progression of skin tumors , 1995, Cell.

[37]  K. A. Lee,et al.  Promoters containing ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene. , 1995, Oncogene.

[38]  C. Denny,et al.  Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene. , 1995, Oncogene.

[39]  M. Ouchida,et al.  The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains. , 1994, Oncogene.

[40]  M. Greenberg,et al.  Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB , 1994, Cell.

[41]  E. Wagner,et al.  Osteoblasts are target cells for transformation in c-fos transgenic mice , 1993, The Journal of cell biology.

[42]  U. Möhle-Steinlein,et al.  A novel target cell for c‐fos‐induced oncogenesis: development of chondrogenic tumours in embryonic stem cell chimeras. , 1991, The EMBO journal.

[43]  A. Sandberg,et al.  Cytogenetic findings in clear cell sarcoma of tendons and aponeuroses. Malignant melanoma of soft parts. , 1991, Cancer genetics and cytogenetics.

[44]  M. Montminy,et al.  Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 , 1989, Cell.

[45]  J. Visvader,et al.  Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. , 1988, Genes & development.

[46]  M. Montminy,et al.  Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[47]  D. Pritchard,et al.  Clear cell sarcoma. A clinicopathologic study of 27 cases , 1983, Cancer.

[48]  F. Enzinger.  Clear‐cell sarcoma of tendons and aponeuroses. An analysis of 21 cases , 1965, Cancer.

[49]  K. M. Mulder,et al.  Knockdown of c‐Fos suppresses the growth of human colon carcinoma cells in athymic mice , 2012, International journal of cancer.

[50]  H. Tsuchiya,et al.  Clear cell sarcoma of tendons and aponeuroses , 2007, Cancer.

[51]  J. Pfeifer,et al.  EWS-ATF1 fusion transcripts in gastrointestinal tumors previously diagnosed as malignant melanoma. , 2005, Human pathology.

[52]  L. Kindblom,et al.  Clear-cell sarcoma of tendons and aponeuroses , 2004, Virchows Archiv A.

[53]  D. Fisher,et al.  Clear Cell Sarcoma Shows Immunoreactivity for Microphthalmia Transcription Factor: Further Evidence for Melanocytic Differentiation , 2001, Modern Pathology.

[54]  J. Neff,et al.  Chromosomal abnormalities in clear cell sarcoma. Implications for histogenesis. , 1990, American journal of clinical pathology.

[55]  N. Birnberg,et al.  A cyclic AMP- and phorbol ester-inducible DNA element , 1986, Nature.

[56]  Lavnikova Ga,et al.  [Clear-cell sarcoma of tendons and aponeuroses]. , 1973, Arkhiv patologii.