Cells talk to each other using a receiver called Notch, and when it malfunctions, it can either drive or suppress cancer depending on the tissue. In T-cell acute lymphoblastic leukemia and breast cancers, too much Notch signal makes cells multiply uncontrollably, forming tumours. But in other cancers, the opposite happens, meaning the instructions Notch sends must differ depending on context. This makes it risky to use drugs that simply shut off Notch entirely—they could damage healthy tissues. This project asks two questions: what normally keeps Notch signalling in check, and what determines the specific instructions Notch gives once activated. The researchers will use fruit flies, which share over 80% of human disease-causing genes, alongside human breast cells. They will read all the genes turned on by Notch in normal tissue versus overgrown tissue, and identify the cellular components that help Notch pick which genes to switch on. This is fundamental science. It will not produce a drug tomorrow. But understanding how Notch’s instructions are coded could eventually allow researchers to design drugs that correct only the harmful signals, leaving healthy Notch function intact. Similar fundamental work on signalling pathways has previously led to targeted cancer therapies.
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To build and maintain our tissues so that they are the correct shape and size it is vital that the building blocks, the cells, are able to talk to one another. They do so via specialized communication devices, one of which uses a receiver called Notch. When Notch receives a signal it then gives the cell instructions about what to do, for example whether or not to multiply. Under normal conditions there are checks and balances in the system to ensure that the cells signal correctly. However, in several types of cancers Notch signalling doesn't function properly. In many of these conditions, including T-cell acute lymphoblastic leukemia and breast cancers, there ends up being too much signal causing the cells to multiply excessively, forming tumours. Surprisingly, in some other types of cancer the converse is the case. This means that the instructions sent by Notch when it receives the signal must be different. It also makes it more difficult to use drug treatments that simply shut off the Notch signal as they could have damaging effects in some tissues. By answering two key questions we hope to identify strategies that could be used to develop more targeted drugs so avoiding these problems. First we aim to discover what are the normal checks that prevent the Notch pathway running out-of control and how these get damaged. Second we will find out what is responsible for coding the instructions sent by Notch once it receives the signal. To do this we will use both the fruit fly and human cells and will undertake large scale analysis that allows us to read all of the instructions, in the form of the genes that are "turned on", in normal tissue and in tissues that grow too much because they have extra Notch activity. In parallel we will use strategies that enable us to find the components in cells that help Notch to pick out which genes to turn on. We use fruit flies because they have a simpler system that we can easily study in the living organism, making it more straightforward to decipher the information, yet they have over 80% of the human disease-causing genes. We then translate our discoveries from fruit-flies into the more complex human breast cells to show their relevance for disease and to identify the best routes towards uses in the clinic.
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