As a tumour stiffens, it physically shields cancer cells from chemotherapy and helps them break away to spread through the body. This project addresses a critical gap: doctors know that stiff tumours resist treatment and metastasise more aggressively, but they do not know which proteins inside cancer cells sense and exploit that mechanical change. Without that knowledge, therapies cannot target the physical environment of the tumour. The researchers will use proteomics to catalogue every protein that changes when tumour matrix stiffens, then use live microscopy to watch how those proteins help cancer cells survive chemotherapy. They will also analyse tissue samples and stiffness scans from head and neck cancer patients—a disease with a 50% relapse rate after treatment. If successful, this work could identify new protein targets for drugs that block the mechanical signals driving metastasis and treatment resistance. It could also give clinicians a simple stiffness-based scan to predict which patients will relapse, enabling more aggressive early treatment. This is fundamental science with a direct clinical pipeline: understanding how physical forces control cell behaviour in a real, aggressive human cancer.
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Solid tumours are complicated multi-factorial tissues made up of lots of different ell types that all contribute to disease progression. The main non-cell component in tumours is called the extracellular matrix. This is a fibrous network of proteins found in all connective tissues in the body, but in tumours is plays a particularly important role in supporting cancer cell survival. The extracellular matrix in most tissues is usually quite soft and pliable but researchers have discovered that in many cancers, this matrix becomes stiffer and this in turn helps cells to grow and move away from the primary tumour site in a process called metastasis. We have discovered some proteins that respond to the changes in the tumour stiffness to help protect cancer cells from damage and help them move away and metastasise. We have also discovered that some tumours become even more stiff when treated with chemotherapy and this can make the tumour grow more and prevent the chemotherapy from killing the tumour cells. However, we still don't know the full picture of which proteins inside cells aide this process. In this project we will use a technique called proteomics to survey all proteins in cells and see how they change in levels and function in response to increasing tumour matrix stiffness. We will use complex microscopy techniques to learn how these proteins help cancer cells evade chemotherapy in live samples and understand how the mechanical environment surrounding tumours corresponds to how immune cells either attack or assist in tumour growth. Finally, we will use all of our data to analyse samples from patient with head and neck cancer, which has a 50% relapse rate after treatment and urgently requires better understanding of disease progression to enable new treatments. By analysing human tissue samples, and also taking special scans of patients to analyse the stiffness of their tumours, we will learn which proteins are changed in patients with stiffer tumours, and whether some of these proteins can provide information to clinicians to treat these patients more effectively. The outcome of our project will provide a much clearer understanding of the relationship between the 'biomechanics' in head and neck cancer tissues and the cells that occupy those tumours. The new information we will uncover will help to design new ways to treat patients and find new targets for future development of new drugs targeting cancer growth and metastasis.
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