In pancreatic ductal adenocarcinoma (PDA), an extensive stromal reaction drives tumour progression and contributes to the lethality of the disease. An understanding of the causes of this desmoplastic 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.

To profile rigidity-induced cellular signalling networks, we have first investigated the sensing of stromal rigidity at the adhesion nexus, the junctional structure that links cells to the extracellular matrix via integrin receptors. Since stromal fibroblasts are the source of much of the desmoplastic response in PDA, our initial approach has been to define tumour-specific alterations in force-sensitive components of the adhesion nexus and rigidity-dependent changes in signalling networks in these cells.

For this purpose, we have used the proximity-dependent labelling method BioID to assemble an in situ adhesome network. Through the use of 16 different BioID baits, most known adhesome components have been identified, together with many potential new candidates. The quantitative changes in this network (a) in response to actomyosin inhibition with blebbistatin and (b) when adhesive substrates of varying rigidity are employed have been determined. These studies suggest effector mechanisms that drive the initial steps of mechanosensing.

To link these mechanisms to signalling outputs, we have performed a whole cell phosphoproteomic analysis of PDA organoids seeded on substrates of varying rigidity. Bioinformatic analysis of the data defined a core signalling network that connected adhesion almost exclusively to cell cycle regulation and DNA damage responses. Furthermore, a stiffness response signature derived from the data correlated with patient outcome. Taken together, the insights from these analyses provide line of sight to future therapeutic strategies.

Biography

Professor Martin J Humphries graduated from the University of Manchester in 1980 and completed his PhD training in 1983, supervised by Dr. Sobhy Ayad. He carried out postdoctoral research at the Howard University Cancer Center, Washington, D.C., USA and at the National Cancer Institute, NIH, Bethesda, MD, USA with Dr. Ken Yamada and Dr. Ken Olden.

In 1988, he was awarded a Wellcome Trust Senior Research Fellowship to return to Manchester. In 1995, he progressed to a Principal Research Fellowship and co-founded the Wellcome Trust Centre for Cell-Matrix Research, which he directed from 2000-2009. From 2008-2016, he was Vice-President & Dean of the Faculty of Life Sciences.

He is a Fellow of the Academy of Medical Sciences and the Royal Society of Biology, and a member of Academia Europaea. He have served as Chair of the Biochemical Society and Vice- President of the Academy of Medical Sciences, and he currently is Senior Independent Member and Chair of BBSRC Council. He have supervised 41 postdoctoral research associates and 59 PhD students. The long-term aim of the research conducted in his laboratory is to elucidate the mechanisms by which adhesion controls cell behaviour. A current focus is the ternary connection between extracellular matrix rigidity, signals transduced by adhesion receptor-associated complexes and cell cycle progression.