Cancer research: fruit flies take it down a notch

You wouldn't think that those pesky flies hovering around your fruit bowl could help scientists understand cancer. Flies don't have cancer, and a fly is, well, just a fly. However, the fruit fly Drosophila melanogaster has been one of scientists' favourite animal models for over a century, and is nowadays used to study many human diseases. New research using fruit flies has now uncovered molecular details in tissue overgrowth that explain some long-standing questions in cancer research.

Why Drosophila? When compared to other lab animals like mice, for instance, flies have many advantages. They are tiny and hence you can grow them anywhere, they are cheap to maintain (in the old days they were fed with rotten bananas) and they breed in just 12 days while mice take 12 weeks. But the most important fact is that, even though flies and humans look very different, most of their genes are the same, or very similar. So while manipulating fly genes in the lab is quite easy, when scientists understand how a gene works in the fly, these discoveries can have significant implications for human medicine.

To study a human disease in flies scientists begin by making them sick. They mutate, or disrupt, the same gene that is known (or suspected) to cause the human disease, and then they try to figure out why meddling with this particular gene causes the disease symptoms, which in flies are called phenotypes. And this is exactly what Sarah Bray's team at the University of Cambridge did to understand the molecular details of tissue overgrowth that may lead to cancer.

In a study published in the January issue of EMBO Journal, the Cambridge scientists introduced in flies a modified version of the Notch gene that makes it overactive, or in other words, the gene is always turned on, and this set off massive tissue overgrowth in the larvae, mimicking what happens in cancer. Notch is a gene that is overactive in many cancers such as breast, lung and cervical cancers, but how Notch activation induces cancer is not understood.

The Notch gene encodes for a protein involved in cell communication. When Notch receives a signal from a neighbouring cell, it becomes activated and instructs specific genes to switch on. Each of these genes does a different job in the cell, such as telling the cell to multiply. The problem is that, with the same signal, Notch can activate many genes, and it is difficult for scientists to predict what the combined effect of all these genes will be for a cell or a tissue. To make matters worse, Notch activation can have opposite cellular outcomes. For instance, in some cases Notch causes tissue overgrowth and cancer, while in others Notch actually stops tissue growth. This paradox has been puzzling scientists for over a decade, and is a major factor hindering progress in Notch cancer research.

To try and solve this problem, Bray's team used genomic approaches to search for genes activated by Notch in the overgrown tumour-like larval tissues. The researchers figured that knowing which genes are abnormally activated by Notch in their simplified 'cancer' fly model might explain the different cellular responses to Notch. And this is exactly what they found. "We found that in a same tissue, Notch activates genes that seem antagonistic" says Alexandre Djiane, leading author in the study. But when they had a closer look the team found that these opposing genes "are actually activated in different subsets of the tissue." Notch activation produced a central region in the tissue where cells divided slowly, surrounded by cells that multiplied very quickly. How does Notch induce these different cellular responses? Djiane explains "this regionalisation of the response is at least in part a consequence of cross-regulation between the different Notch targets themselves". Notch can not only activate different genes in the same tissue, but some genes can also interfere with one another, in a sort of battle between genes where the winner gets to tell the cell what to do.

But are these newly found genes involved in cancer? By comparing their results with cancer patients' databases, the authors found that several of the genes abnormally activated by Notch in the fly overgrown tissue were overactive in human cancers. This is a good indication that the genes identified in the fly may be potential candidate cancer-promoting genes in humans. But the researchers went even further. They used genetic tricks that turned these genes up or down to test what they actually do in living flies, and found that about two thirds "play a role in tissue growth and mediate the effect of Notch," says Djiane.

"The advantage of the fruit fly is, as demonstrated in this work, that several of these candidates can be rigorously tested via fast and efficient genetic testing to confirm the functional importance of each target gene" says Marcos Vidal, a cancer biologist at the Beatson Institute for Cancer Research in Glasgow who was not involved in this study. "This kind of research complements the one performed directly from clinical samples and cell lines."

Current cancer drugs targeting Notch have side effects because Notch is critical for many biological processes. Vidal says "[...] direct inhibition of Notch appears to have undesired side effects and therefore may not be an ideal therapeutic target itself. On the other hand, the gene targets specifically regulated by Notch in tumorous growth identified in this study, could potentially be better therapeutic targets in Notch-driven cancers."

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