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Updated: Mar 11, 2026
The Drosophila Imaginal Disc Tumor Model: Visualization and Quantification of Gene Expression and Tumor Invasiveness Using Genetic Mosaics
Published on: October 6, 2016
Functional exploration of colorectal cancer genomes using Drosophila
Erdem Bangi1, Claudio Murgia2, Alexander G S Teague1
1Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Annenberg 25-40, New York, New York 10029, USA.
Abstract:
The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. Here we use Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, we identify a mechanism of resistance for the PI3K pathway inhibitor BEZ235. We use this data to identify a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity we term 'induced dependence'. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies.
Insights
Developing new cancer drugs is hard because tumors have many genes. This study used fruit flies to create colon cancer models, finding a new therapy that overcomes drug resistance by making cancer cells dependent on the treatment.
Area of Science:
- Genetics
- Oncology
- Drug Discovery
Background:
- Human tumors are genetically complex, posing challenges for effective cancer drug discovery.
- The Cancer Genome Atlas (TCGA) provides valuable patient data for understanding tumor genomics.
Purpose of the Study:
- To develop multigenic Drosophila models of colon cancer using TCGA data.
- To investigate emergent drug resistance in these models.
- To identify novel therapeutic strategies to overcome resistance.
Main Methods:
- Generated 32 multigenic colon cancer models in Drosophila referencing human cancer genomes.
- Utilized patient data from The Cancer Genome Atlas for model creation.
- Investigated drug resistance mechanisms, specifically for PI3K pathway inhibitor BEZ235.
- Developed and tested a combinatorial therapy termed 'induced dependence'.
Main Results:
- Drosophila models recapitulated key features of human colon cancer, often as emergent properties.
- Multigenic models demonstrated emergent resistance to various cancer drugs.
- Identified a resistance mechanism for BEZ235, leading to the development of a novel combinatorial therapy.
- The 'induced dependence' therapy proved effective in human tumor cells, xenografts, and mouse models of colorectal cancer.
Conclusions:
- Multigenic animal models referencing cancer genomes are effective for discovering novel targeted therapies.
- The 'induced dependence' strategy offers a promising approach to overcome drug resistance in cancer treatment.
- This study highlights the utility of Drosophila as a model system for complex cancer biology and therapeutic development.
