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22 (21): 5769-5779

Copyright © 2003 by the European Molecular Biology Organization.

scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila

Anthony M. Brumby, and Helena E. Richardson1

Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, Victoria, Australia, 8006 1 Corresponding author: helena.richardson{at}petermac.org

Abstract: 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.

Key Words: Keywords: cell cycle/cell death/cell polarity/cooperative tumorigenesis/Drosophila

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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882