Editors' ChoiceTumorigenesis

A Scribbled Path to Neoplasia

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Science's STKE  11 Nov 2003:
Vol. 2003, Issue 208, pp. tw439
DOI: 10.1126/stke.2003.208.tw439

Cancer generally involves the dysfunction of both oncogenes and tumor suppressors and arises in the context of surrounding normal tissues. Brumby and Richardson grew somatic clones of mutant cells surrounded by normal Drosophila eye disc tissue as an in vivo model system in which to investigate the role in tumorigenesis of scribble, a Drosophila tumor suppressor that is required for the development of epithelial polarity. During larval eye development, clonal cells lacking scribble overproliferated and lost their normal columnar shape and their apical-basal polarity. Moreover, both scribble clones and adjacent wild-type cells showed elevated levels of cyclin E. In adult eyes, however, little scribble tissue remained. Removing the surrounding wild-type tissue, either by expressing Hid, which promotes apoptosis in Drosophila, or by using a homozygous cell lethal mutation, resulted in scribble cell overgrowth. The authors expressed both a constitutively active form of c-Jun N-terminal kinase (JNK) kinase (Hemipterous, JNKK) and a dominant negative form of the JNK homolog Basket to implicate the JNK pathway in elimination of the mutant tissue. Thus, the surrounding normal tissue appeared to eliminate the scribble tissue through JNK-mediated apoptosis. Activated forms of Ras or Notch expressed in scribble clones promoted massive synergistic hyperproliferation, whereas activation of Hedgehog, Wingless, or Dpp signaling pathways did not. The authors proposed a multiple-hit model for cooperative tumorigenesis in Drosophila that emphasized the importance of regulators of epithelial polarity.

A. M. Brumby, H. E. Richardson, scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769-5779 (2003). [Abstract] [Full Text]

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