title: The Drosophila Netrin receptor frazzled/DCC functions as an invasive tumor suppressor.
abstract: BACKGROUND
  Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development.
  
  
  RESULTS
  Most fra loss of function clones are eliminated during development. However, when mutant clone cells generated in the developing eye were rescued from death, partially differentiated eye cells were found outside of the normal eye field, and in extreme cases distant sites of the body. Characterization of these cells during development indicates that fra mutant cells display characteristics of invasive tumor cells, including increased levels of phospho-ERK, phospho-JNK, and Mmp-1, changes in cadherin expression, remodeling of the actin cytoskeleton, and loss of polarity. Mutation of fra promotes basement membrane degradation and invasion which are repressed by inhibition of Rho1 signaling. Although inhibition of JNK signaling blocks invasive phenotypes in some metastatic cancer models in flies, blocking JNK signaling inhibits fra mutant cell death, thereby enhancing the fra mutant phenotype.
  
  
  CONCLUSIONS
  The results of this investigation provide the first direct link between point mutations in fra/DCC and metastatic phenotypes in an animal model and suggest that Fra functions as an invasive tumor suppressor during Drosophila development.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Raclin-Carmichael Hall, 1234 Notre Dame Ave, South Bend, IN 46617, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: VanZomeren-Dohm
authors.forename: Joseph
authors.initials: J
authors.lastname: Sarro
authors.forename: Ellen
authors.initials: E
authors.lastname: Flannery
authors.forename: Molly
authors.initials: M
authors.lastname: Duman-Scheel
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D016147:Genes, Tumor Suppressor; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C081481:Rho protein, Drosophila; D025521:Tumor Suppressor Proteins; C000617310:fra protein, Drosophila; D048670:MAP Kinase Kinase 4