Group leaders: Alba Diz-Muñoz and Michael Platten

Our research interest

Brain tumours, particularly gliomas, are associated with a poor prognosis and frequently resist standard therapy. Due to their infiltrative nature and ability to form networks they cannot be controlled by localized therapies such as surgery and radiotherapy.

Despite the demonstrated importance of tissue mechanics in cancer, and the immense promise that it holds for the identification of new therapeutic targets, our understanding of the molecular basis of brain mechanics is limited. Moreover, the roles mechanical properties and alterations of the extracellular matrix (ECM) play in dictating immune responses in brain tumours are not well understood.

Background

Immunotherapies aimed at activating tumour-specific T-cells, such as vaccines, or at delivering T cells to tumours, such as chimeric antigen receptor T-cell therapy, are promising. However, tumours are often poorly infiltrated by T-cells. This lack of infiltrative capacity has largely been attributed to immunosuppressive mediators and niche-specific microenvironmental factors such as hypoxia and acidification. But in addition, tumours are often surrounded by a high-density extracellular structure, which constitutes a protective wall. In fact, tumour stiffness provides an instructive environment that cells sense and react to, with elevated stiffness predictive of more metastases and poor overall survival in several cancer types.

Goals

With ECM-brain we aim to shed light on this next frontier in cancer treatment via an in-depth multifaceted study of physical barriers in brain tumor tissue. Such barriers are an important yet still largely uncharacterized component of the tumour microenvironment that likely impairs effective immunotherapy. Our interdisciplinary approach combines the analysis of tumour tissue using light and atomic force microscopy with high-performance spatial omics tools to gain a comprehensive knowledge of the impact of tissue stiffness and ECM properties on T cell phenotypes and function.

Research focus

• To evaluate tumour stiffness and perform spatial transcriptomics in healthy and brain tumour tissue in order to gain an understanding of the molecular basis of brain stiffness.
• To validate key ECM components as determinants of T cell infiltrativeness and functionality in brain tumour tissue.
• To perturb specific ECM factors in preclinical models (mouse glioma models and human glioma organoids) with the goal to increase infiltrativeness and functionality of brain tumour-targeting T cells, as we and others have shown that so called mechanomedicines can prolong patient survival in cancer.