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

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.

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…In this regard, the CagA-PAR1-SHP-2 complex has a dual function; disruption of the epithelial polarity and aberrant activation of the Ras-MAPK pathway, indicating that the protein complex coordinates cell polarity defects and oncogenic signaling to promote epithelial cell transformation (Saadat et al, 2007). Such functional cooperativity has already been indicated by the observation that tumors induced by an oncogenic Ras in Drosophila do not have metastatic potential, whereas those induced by oncogenic Ras under the condition of loss of heterozygosity for lgl, dlg and scrib show more malignant phenotypes and frequently metastasize (Brumby and Richardson, 2003;Pagliarini and Xu, 2003).…”

Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model

“…Recently, Drosophila tumor models have been established that are based on defined and reproducible genetic manipulation of tumor suppressor and oncogenes (Brumby and Richardson, 2003;Pagliarini and Xu, 2003). These models consist of cells that have defective cell polarity and activated Ras signaling.…”

“…Loss of polarity is induced by loss of Scribble (Scrib), which is required for apico-basal polarity together with Discs large (Dlg) and Lethal giant larvae (Lgl) (Stewart et al, 1972;. Ras signaling was augmented through overexpression of a constitutively active version of Ras, Ras V12 (Brumby and Richardson, 2003;Pagliarini and Xu, 2003). Cells that are mutant for scrib and simultaneously express Ras V12 proliferate in an uncontrolled manner, pile on top of each other (neoplastic growth) and gain the ability to migrate into surrounding tissues (Brumby and Richardson, 2003;Pagliarini and Xu, 2003).…”

Drosophila in cancer research: to boldly go where no one has gone before

“…Strikingly, they found that disruption of cell polarity synergized with expression of Ras V12 , and gave rise to metastatic tumors that mimicked many characteristics of human cancers. Importantly, clonal loss of scrib and cell polarity alone resulted in poorly growing cells that were eventually eliminated from the tissue, and although Ras V12 expression caused modest hyperplasia, Ras V12 expression in scrib mutant cells not only reversed their growth defects, but synergized with loss of scrib producing highly proliferative cells that formed neoplastic cell masses able to migrate into adjacent tissues (Brumby and Richardson, 2003;Pagliarini and Xu, 2003). This emergent phenotype would not be predicted from the phenotypes of Ras V12 or scrib single mutant cells alone.…”

“…The MARCM technique can produce clones of GFP-'marked' cells that are homozygous mutant in a gene and at the same time overexpress one or more other transgenes or dsRNAi of interest. The groups of Tian Xu and Helena Richardson used the MARCM system to elucidate the role of cooperation between multiple genetic events to promote neoplastic growth and metastasis in Drosophila (Figure 1; Brumby and Richardson, 2003;Pagliarini and Xu, 2003). In particular, they explored an interaction between disruption of apical-basal cell polarity, a defect that promotes the epithelial to mesenchymal transition often associated with cancer, by introducing a mutation in the neoplastic tumor suppressor gene scribble (scrib), which encodes a conserved scaffold protein that is essential for the maintenance of cell polarity (Humbert et al, 2008), and concurrent overexpression of a hyperactive version of the Ras oncogene (Ras V12 ), which is frequently observed in aggressive human cancers.…”