CANCERPATHWAYS

Developmental Molecular Pathways in Drosophila as a Model for Human Cancer

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 Obiettivo del progetto (Objective)

'Cancer is often characterized as a disease of signal transduction pathways, since it is frequently associated with inappropriate activation of such pathways. Indeed, new therapeutic approaches in cancer therapy, such as Herceptin, frequently target signaling pathway components to revert their pathophysiological aberrations. Most oncogenic pathways have been highly conserved throughout evolution with Drosophila representing a particularly powerful genetic model for the analysis of such signaling cascades. These cancer pathways include Wnt, Notch, Hippo and JAK/STAT pathways. The analysis of signaling pathways in Drosophila is facilitated by the availability of a broad range of genetic tools, a completely sequenced genome and the availability of genome-wide collections of RNAi reagents. Within this project, we will establish high-throughput cell-based assays for regulators of the major developmental oncogenic signaling pathways. Cell-based assays for signaling pathways will be screened using genome-wide RNAi and small molecule compound libraries to identify new components, regulators and targets. Suppressor/enhancer screens in cultured cells will be used to identify small molecular compounds that interfere with the activity of specific signaling pathways and in vivo models of signaling pathways will be established to test the activity of drugs using developmental and tumorogenic phenotypes. By integrating and standardizing data from most important cancer relevant signaling pathways and combining them with powerful bioinformatics tools, we expect to get highly validated information on possible drug targets and lead substances. The collaborative project integrates recent technological advances, such as genome-wide RNAi libraries for cell-based and in vivo assay models that were developed by the participants, as well as computational approaches and databases to integrate and disseminate the information obtained during the project.'

Introduzione (Teaser)

A European consortium set out to identify novel cancer targets and small molecules using the fruit fly as a model organism. By integrating technological advances in the field and developing novel bioassays CANCERPATHWAYS scientists were able to conduct high-throughput screening (HTS) of cancer-associated pathways and to discover novel cancer targets and compounds with anti-cancer therapeutic potential.

Descrizione progetto (Article)

One of the hallmarks of cancer development is uncontrolled cell proliferation. Various signalling pathways (Wnt, Notch, Ras, Hippo, PI3K and JAK/STAT) have been linked with cancer onset and progression, but the full potential of signalling molecules as therapeutic targets has yet to be explored.

In this context, the EU-funded project 'Developmental molecular pathways in Drosophila as a model for human cancer' (CANCERPATHWAYS) brought together leading scientific experts in the field to produce fundamental advances in our understanding of cancer biology. The consortium used the fruit fly Drosophila melanogaster, which represents a powerful model system for studying oncogenic pathways.

To study the functional outcome of individual genes in cancer development and identify novel targets of oncogenic signalling pathways, the scientists generated genome-wide RNA interference (RNAi) reagents targeting nearly every gene in the Drosophila genome. For the design and evaluation of these genome-wide reagents, the software algorithm http://www.nextrnai.org (NEXT-RNAi) was developed. Based on this in vitro RNAi library, transgenic Drosophila in vivo RNAi lines were created for nearly 12 000 genes and were made publically available through the Vienna Drosophila RNAi Center (VDRC).

The CANCERPATHWAYS consortium developed novel bioassays for the screening of genome-wide RNAi and small molecule compound libraries and for assessing their impact on cell fitness and specific pathway activities. Large-scale RNAi screening led to the identification of novel therapeutic target genes. High-throughput compound screens resulted in the identification of novel candidate molecules that interfered with the activity of oncogenic signalling pathways.

Phenotypic screening of cell lines was also performed by image-based techniques, which enabled the simultaneous analysis of multiparametric features. Analysis software developed in the project was made available as Bioconductor/R packages. Experimental work led for instance to the identification of novel mechanisms that control Notch signalling as well as transcriptional targets of the Drosophila JAK/STAT pathway as effectors of haematopoietic tumour formation.

Collectively, the work conducted by CANCERPATHWAYS proved that Drosophila constitutes a valid model for rapid, high-throughput anti-cancer drug screening and target discovery. The powerful tools led to the identification of multiple novel key factors involved in cancer development that would not have otherwise been identified by traditional 'top down' approaches. The brochure is available http://www.cancerpathways.eu/Brochure/ (here).