ZF-CANCER

Developing high-thoughput bioassays for human cancers in zebrafish

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Recently the zebrafish has emerged as a new important system for cancer research because the zebrafish genome contains all orthologs of human oncogenes and forms tumors with similar histopathological and gene profiling features as human tumors. The zebrafish provides an in vivo vertebrate model for identifying novel mechanisms of cancer progression and for development of new anticancer compounds in a time- and cost-effective manner. The ZF-CANCER project aims to develop high-throughput bioassays for target discovery and rapid drug screenings applicable in preclinical validation pipelines. Fluorescently labelled human and zebrafish cancer cells will be implanted (xenogenic and allogenic transplantation) into zebrafish embryos transgenic for a GFP-vascular marker and quantitative, multi-colour fluorescent intravital bio-imaging of tumour progression will be set up as the readout. Because of its amenability to genetic manipulation and optical transparency, the zebrafish is currently the only vertebrate model that allows the simultaneous in vivo imaging of all hallmarks of cancer progression including cell survival, proliferation, migration and induction of angiogenesis. The combination of visual, non- invasive monitoring in translucent host embryos with powerful RNA interference technology, successfully developed for human cancer cells will enable identification of novel targets in a wide variety of human cancers. Automation of these fluorescent readouts will accelerate the screening process with chemical libraries to discover new compounds involved in different aspects of cancer progression and inhibition. In the case study, a selected panel of genes and lead compounds will be screened on a high-throughput platform, possibly resulting in the identification of important anti-tumour drugs relevant for human cancer therapy. Fundamental knowledge, tools and technical expertise gained from ZF-CANCER will be commercially exploited by one company and two high-tech SMEs.'

Introduzione (Teaser)

An alternative animal model based on zebrafish was developed for studying cancer progression and identifying drug targets and anti-cancer lead compounds. The ZF-Cancer model holds the potential to speed up the screening of anti-cancer therapies.

Descrizione progetto (Article)

Zebrafish have emerged as a new model for studying oncogenesis, mainly because its genome contains all orthologues of human oncogenes and forms tumours with similar histopathological and gene profiling features to human tumours. Additionally, the availability of many transgenic zebrafish combined with their optical transparency make it a powerful model for imaging cancer progression.

The scientific objective of the EU-funded 'Developing high-thoughput bioassays for human cancers in zebrafish.' (ZF-Cancer) project was to develop clinically relevant high-throughput bioassays for cancer progression. These were envisioned to be exploited in the pre-clinical validation of novel chemical and genetic cancer targets.

This system had the major advantage of direct visualisation of tumour growth and metastasis in an optically transparent vertebrate model organism. The transparent zebrafish embryos coupled with ribonucleic acid (RNA) interference technology enabled the identification of novel gene targets that drove tumour progression in a range of cancers. The inoculation of fluorescently-labelled human cancer cells allowed for delineation of the fundamental hallmarks of cancers.

Automation of these fluorescent readouts would accelerate the process of screening of chemical libraries for the discovery of new compounds involved in different aspects of cancer progression and inhibition. To this end, these technologies were integrated in a robotic setup, thereby allowing full automation of the process from tumour cell implantation and drug treatment, to bio-imaging and data analysis.

Special emphasis was given to kinase inhibitors that sensitised p53 mutant embryos against irradiation-induced apoptosis and angiogenesis development. Potent anti-cancer kinase drug targets were discovered with this approach and pilot compounds were screened.

The ZF-Cancer zebrafish embryo model has the potential to accelerate the lead time of anti-tumour drugs considerably, rendering the entire process more cost effective and efficient. Apart from obvious benefits for research, the zebrafish model could extend to pharmaceutical-oriented applications.