scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila
Open accessAbstract
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.
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Loss of polarity (scrib) alone is insufficient to induce aggressive growth in somatic clones.
“Loss of polarity ( scrib ) alone is insufficient to induce aggressive growth in somatic clones (Fig. 1, S1) (8,9,12,30)”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [9]
Activating the JNK pathway in scribble mutant cell clones is required for scribble cell elimination, acting via autonomous and nonautonomous mechanisms.
“Activating the JNK pathway in scribble mutant cell clones is required for scribble cell elimination, acting via autonomous and nonautonomous mechanisms (Brumby and Richardson, 2003; Uhlirova et al., 2005; Igaki et al., 2006).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Brumby and Richardson, 2003
Clonal patches of scribble mutant cells do not hyperproliferate but instead are eliminated by competition with surrounding wild-type cells.
“Mosaic analysis of imaginal discs revealed that clonal patches of scribble mutant cells do not hyperproliferate but instead are eliminated by competition with surrounding wild-type cells (Brumby and Richardson, 2003; Igaki et al., 2006, 2009; Yamamoto et al., 2017).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Brumby and Richardson, 2003
Clones mutant for scribble lose apical-basal polarity and die, but when RasV12 is coexpressed they develop into large tumors that are much more aggressive than those expressing RasV12 alone.
“Clones mutant for scribble lose apical–basal polarity and die, but when RasV12 is coexpressed they develop into large tumors, which are much more aggressive than those expressing RasV12 alone.”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Brumby and Richardson, 2003
JNK signaling also acts to suppress hyperproliferation of scribble mutant clones.
“JNK signaling also acts to suppress hyperproliferation of scribble mutant clones (Brumby and Richardson, 2003; Igaki et al., 2009; Chen et al., 2012).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Brumby and Richardson, 2003
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“JNK signaling also acts to suppress hyperproliferation of scribble mutant clones (Brumby and Richardson, 2003; Igaki et al., 2009; Chen et al., 2012).”
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- Authors
- Brumby, A. M., & Richardson, H. E.
- Affiliations
- Peter MacCallum Cancer Centre (AU)
- Corresponding author
- Richardson, Helena E.
- Venue
- The EMBO Journal
- Published
- 2003-11-03
- Volume
- 22
- Issue
- 21
- Pages
- 5769-5779
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC275405
- OpenAlex
- W1992418538
- Semantic Scholar
- 2f8590ce00e5d966486101a4dbb9a7a40b573228
- Cited by
- 628
- References
- 47
- Citations by year
- 2026: 19 · 2025: 38 · 2024: 32 · 2023: 26 · 2022: 36 · 2021: 34 · 2020: 28 · 2019: 43 · 2018: 29 · 2017: 34 · 2016: 27 · 2015: 38 · 2014: 33 · 2013: 44 · 2012: 30
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Scribble, oncogenic Ras, notches, tumor suppressor, cyclin E, JNK signaling, cell death, epithelial tumors, eye disc, Drosophila
- MeSH terms
- Animals, Drosophila, Eye, Membrane Proteins, Models, Biological, Mutation, Neoplasms, Experimental, Genes, ras, Up-Regulation, Gene Expression Regulation, Neoplastic, Apoptosis, Genes, Insect, Cyclin E, Mitogen-Activated Protein Kinases, Drosophila Proteins, JNK Mitogen-Activated Protein Kinases, Receptors, Notch
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