Multi-scale mechanochemical signals regulating cancer cell survival and invasive potential

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.

Our Programme will address an important emerging concept in cancer biology concerning the impact of tumour biomechanics on head & neck cancer cell adaptation and response to therapy. Our own data, and that of other groups suggest mechanical forces in the tumour microenvironment can enable tumour cell adaptation through changes in levels and localisation of cytoskeletal-associated proteins. This leads to altered nuclear envelope integrity, DNA damage response, exosome secretion and immune cell function. However, the key cytoskeletal-associated proteins involved in these responses remain unknown, and we hypothesise that identifying these proteins and analysing their function in vitro and patient samples will lead to new biomarkers and targets for therapeutic intervention. We will adopt a multi-disciplinary approach to analyse human head and neck cancer cell responses to mechanical changes using longitudinal imaging of 3D culture models with tuned stiffness that reflect those seen in patients. Within these models we will firstly explore changes to the subcellular distribution of the proteome in response to increasing stiffness, using unbiased multi-plexed proteomics and functional imaging to analyse cell viability, invasion and DNA damage. We will determine how target proteins already identified by us impact on these events, and how biomechanics alter exosome secretion. We will further define how these changes affect cancer cell resistance to chemotherapy, tumour-immune cell interactions using 3D co-culture models and functional imaging. Finally, we will align our discoveries with an ongoing clinical trial to understand whether changes to our novel mechano-responsive targets correlate with patient tumour mechanics and the functional importance of these in patient-derived organoids. Data arising from our study will greatly enhance our understanding of tumour cell responses to biomechanical changes and identify new biomarkers and targets for therapeutic intervention.