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Modelling Cancer Traits in Drosophila

Final Report Summary - FLIESCAN (Modelling Cancer Traits in Drosophila)

FliesCan has explored the potential of the vinegar fly Drosophila melanogaster to implement new experimental models to tackle cancer. Despite obvious anatomical and physiological differences, malignant tumours in humans and flies are made of cells that derail from their normal course of development, grow out of control, become immortal and invasive, and kill the affected individual. These simple considerations and the well-established advantages of Drosophila as an experimental model, in which sophisticated functional genetic and molecular biology assays can be performed at a rate and with a level of detail that are unmatched by current mammalian models, provide the rational behind FliesCan.

The first of the two main objectives of FliesCan was to identify new paths of intervention to inhibit tumour growth. To this end we have tested thousands of genes for their potential to inhibit brain tumours and found over a hundred of such potential therapy targets. Many of these were not suspected to be relevant for cancer before and may provide leads for the development of new therapies. Remarkably, we have also identified Drosophila genes that are closely related to several human genes that have been known for decades to be aberrantly expressed in different types of cancer and thus suspected to play a role in the disease. These findings open up new experimental approaches to unveil the molecular details of how these genes contribute to malignancy.

A significant fraction of the targets to inhibit tumour growth identified by FliesCan are genes that are expressed only in testes or ovaries in healthy individuals, but become aberrantly expresses in somatic tissues that develop as malignant tumours. Such genes are referred to as Cancer/Testis (CTs) in human oncology. Because they do not play any role in healthy somatic tissues, CTs are particularly suitable as targets for therapy.

We have also carried out in vivo screens to identify tumour-inhibitory compounds. We have found two such hits and, importantly, optimised the screening procedure such that one single investigator can test over a thousand chemical compounds on tumour-bearing living Drosophila larvae in less than a month.

Another major objective of FliesCan was to assess the extent to which certain genomic lesions that are common in human cancer are also present in fly tumours. To this end we have sequenced the entire genomes of a set of fly tumour samples taken at different stages of tumour growth. We have found that genomic lesions that are common in human cancer like changes in single nucleotides or in gene copy number are also present in Drosophila malignant tumours at rates that are tumour-type dependent.

We have also constructed transgenic strains carrying fluorescent probes that label the onset of aneuploidy. Introducing these probes in a fly brain tumour, we have found that the onset of chromosome instability occurs after the tumour has started to grow and is therefore a consequence and not a cause of malignant growth in this type of tumour.

Altogether, these results yield new valuable insight into the molecular cell biology of malignant growth and unveil new targets that hold great potential as leads to develop new therapies.