scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila.
Cancer is a multistep process involving cooperation between oncogenic or tumor suppressor mutations and interactions between the tumor and surrounding normal tissue. Here we present the first description of cooperative tumorigenesis in Drosophila, by using a system that mimics the development of tumors in mammals. We have used the MARCM system to generate mutant clones of the apical-basal cell polarity tumor suppressor gene, scribble, in the context of normal tissue. We show that scribble mutant clones in the eye disc exhibit ectopic expression of cyclin E and ectopic cell cycles, but do not overgrow due to increased cell death mediated by the JNK pathway and the surrounding wild-type tissue. In contrast, when oncogenic Ras or Notch is expressed within the scribble mutant clones, cell death is prevented and neoplastic tumors develop. This demonstrates, for the first time in Drosophila, that activated alleles of Ras and Notch can act as cooperating oncogenes in the development of epithelial tumors, and highlights the importance of epithelial polarity regulators in restraining oncogenes and preventing tumor formation.
Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, Victoria 8006, Australia.
Anthony M
AM
Brumby
Helena E
HE
Richardson
D000818:Animals; D017209:Apoptosis; D019927:Cyclin E / Q000235:genetics; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology; D005123:Eye / Q000254:growth & development; D015972:Gene Expression Regulation, Neoplastic; D017344:Genes, Insect; D011905:Genes, ras; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics; D051880:Receptors, Notch; D015854:Up-Regulation
D019927:Cyclin E; D029721:Drosophila Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C404683:Scrib protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases