Martin Humphries, BSc PhD FMedSci
Adhesion signalling in pancreatic ductal adenocarcinoma
My laboratory started by identifying mechanisms of adhesion-dependent growth control and melanoma cell adhesion and metastasis, progressed to structure-function analyses of integrin and syndecan receptors, and is currently using proteomic approaches to define signalling mechanisms originating at the adhesion nexus. This is the structure that connects the extracellular matrix to the intracellular cytoskeleton. Over the past five years, we have made discoveries in three areas: the receptor-transduced signals that control normal and tumour cell migration and invasion, the identity of force sensors within cells, and the mechanisms of microenvironmental sensing in disease.
Until recently, attempts to isolate the adhesion nexus and then investigate its function have been frustrated because the nexus is a membrane-cytoskeleton junction and not a discrete organelle. However, we have overcome this hurdle by developing methods to isolate the junction and by establishing a proteomic workflow to interrogate its function. This major technical advance has allowed us to apply the power of proteomic analyses to identify changes in the composition of the adhesion nexus.
Our current research is focused on the link between adhesion signalling and cell proliferation using pancreatic ductal adenocarcinoma (PDAC) as a model. In PDAC, an extensive stromal reaction drives tumour progression and contributes to the lethality of the disease. An understanding of the causes of this response, and the consequent effects of a highly rigid stromal extracellular matrix on tumour cell phenotype, would therefore be a pivotal step in the quest to improve patient outcomes. Methods are now available to investigate force sensing in vivo, so it is timely to determine how stromal rigidity drives tumour proliferation.
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.
Tel: +44 (0) 161 275 5071
Recent key publications
Horton, E.R., Byron, A., Askari, J.A., Ng, D.H.J., Millon-Frémillon, A., Robertson, J., Koper, E.J., Paul, N.R., Warwood, S., Knight, D., Humphries, J.D. and Humphries, M.J.(2015). Definition of a consensus integrin adhesome and analysis of its dynamics during adhesion complex assembly and disassembly. Nature Cell Biol. 17, 1577-87.PubMed
Robertson, R., Jacquemet, G., Humphries, J.D., Byron, A., Jones, M., Warwood, S., Selley, J., Knight, D. and Humphries, M.J. (2015). Defining the phospho-adhesome: phosphoproteomic analysis of integrin signalling. Nature Commun. 6, 6265. PubMed
Byron, A., Askari, J.A., Humphries, J.D., Jacquemet, G., Koper, E.J., Warwood, S., Choi, C.K., Stroud, M.J., Chen, C.S., Knight, D. and Humphries, M.J. (2015). A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting. Nature Comm. 6, 6135. PubMed.