Current research programmes

Current research programmes

Three central hypotheses will be tested:

1. That the sensing of stromal rigidity originates at the adhesion nexus, the junctional structure that links cells to the extracellular matrix via integrin receptors.

2. That high stromal rigidity impedes the changes in cell architecture needed for accurate segregation of chromosomes during mitosis and that mechanical cues in the extracellular environment are linked to checkpoint-dependent control of the cell cycle.

3. That driver mutations in cancers lead to a rewiring of signalling networks, one outcome of which is evasion of these checkpoint control mechanisms. The desmoplastic response therefore forces proliferation under unfavourable circumstances and accelerates tumour progression.

Our immediate objectives for the next five years will be to:

1. Define tumour-specific alterations in force-sensitive components of the adhesion nexus.

2. Determine the mechanisms whereby rigidity influences cell proliferation.

We will build on our knowledge base of integrin-mediated adhesion and the specialist methodologies that we have pioneered to elucidate integrin function, and apply both to models of pancreatic adenocarcinoma. We will establish new techniques for global analyses of the adhesion nexus in three-dimensional pancreatic organoids (using proximity labelling and mass spectrometry) and define how variations in extracellular rigidity initiate signalling at this site to influence cell cycle progression. We will then determine the effects of perturbing candidate molecules in organoids and employ molecular cell biology approaches to pinpoint how the sensory mechanisms vary between wild type and tumour cells.

The outcomes of the programme will advance our understanding of cancer in two ways: by defining how the adhesive stromal microenvironment influences tumour cell proliferation, and by identifying potential clinical targets. In studies beyond the scope of this programme, perturbation of tumour cell-specific alterations in the rigidity-sensing process will be examined in relevant pre-clinical models. Agents that target the evasion of this sensory system could then be used to sensitise tumours to mitotic inhibitors or other chemotherapeutics.

Current research programmes – right hand column

Force-sensitive consensus adhesome components

Read the full text of the publication, “Mechanosensitivity of integrin adhesion complexes: role of the consensus adhesome“.