Programming the Notch Response

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.

Notch signalling is critical for many aspects of development, from stem cell maintenance to epithelial growth control, and its dysregulation underlies many diseases, especially cancers. These conditions of pathological Notch signalling reveal that there must exist mechanisms that normally keep the Notch pathway in check, which are defective in these diseases. Furthermore, although Notch activity promotes tumourigenesis in many contexts, including T-cell acute lymphoblastic leukaemia and breast cancers, in others Notch acts to suppress tumours, making it problematic to rely on general Notch inhibitors for therapeutic intervention. It is important therefore to discover how different subsets of genes are selected for Notch regulation to account for the disparate outcomes of Notch activity.

Our goal is to use a combination of genomic, genetic and biochemical approaches in Drosophila and in human cells to discover the fundamental mechanisms that programme different Notch responses. As Notch acts directly to change gene expression, our primary focus is on the network of genes that are Notch-regulated in different contexts, including tissue hyperplasia. We have two major aims: (1) to discover the mechanisms that normally attenuate Notch signalling in different tissues and how this machinery is disrupted in disease models (2) to elucidate how genes are selected to be Notch-responsive, yielding tissue-specific differences in the outcome of Notch signalling.

Our results will uncover general principles that explain how these diverse effects of Notch activation arise in tissue development and in different types of cancers, especially breast cancers. In doing so they will identify mechanisms of attenuation and of gene selection that are indicative of particular disease outcomes, permitting better diagnosis, and suggest strategies for targeted therapies to avoid the serious side effects from more general Notch inhibitors.

Beneficiaries:
-Industry involved in pharmaceutical research and drug development.
-Medical profession involved in treating Notch related diseases including cancers
-Business, industrial and public sector recruiting graduate level staff.
-The general public and schools, through our involvement in public engagement.

Benefits to industry will come from the scientific results and the methodologies we develop:
Notch pathway is a major target for cancer and other therapeutics. Increased knowledge about the mechanisms can lead to novel approaches for targeting the pathway and can be important in informing about unforeseen side effects. For example, our results should improve the ability to "read" better the types of targets that could be activated in a particular disease context, important because the outcomes can be very different (e.g. tumour promoting versus tumour suppressing). They could also identify novel protein:protein interactions that would be a good substrate for drug developments. Benefit is likely to be realized in the longer term and it would impact especially on enhancing quality of health.

Benefits to medicine will come from the scientific results and the insights into clinically relevant mechanisms:
A better understanding of the types and functions of Notch targets and how they are selected could be extremely valuable in diagnostic strategies because classical Notch targets (e.g., HES1) do not necessarily appear to be modulated in patient tissues. Results will also suggest new possibilities to improve on therapies targeting the Notch pathway. Currently, the main strategies use small molecule inhibitors of gamma-secretase and have serious side effects such as goblet cell metaplasia, as well as off target effects. The discovery of novel regulatory mechanisms in a subset of tissues could lead to more targeted therapies to overcome these problems.

Benefits to business, industrial and public sector recruiting graduate level staff will come from the development of relevant research sills and professional skills:
The project's diverse nature ensures that the staff will acquire a broad range of technical skills (high-end genomic and molecular biology techniques, computational approaches for working with large data sets), which will be applicable in wide range of life sciences, pharmaceutical, computational employment. Further gains come from our international collaborations, enhancing the skills training and exposure. Alongside technical skills, staff will at the same time develop generic professional skills e.g. presentational skills; writing skills; data handling, including statistics; generic computational skills; project management. Evidence of our track record in this aspect comes from subsequent employment of staff from our groups (e.g. investment banking, parliamentary advisor, publishing, venture capital advisor).

Benefits to the general public and schools, through our involvement in public engagement:
We have been involved in communicating modern scientific methodologies and approaches to the wider community. These activities will be extended to encourage scientific understanding and to extend the concepts from our research into other fields. The University of Cambridge provides excellent support for public dissemination of research through the Office of Community Affairs, including the Cambridge Science Festival, and we shall encourage the researchers to participate in these activities.