In pancreatic ductal adenocarcinoma, 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. Methods are now available to investigate force sensing in vivo, so it is timely to determine how stromal rigidity drives tumour proliferation.
Stromal rigidity as a driver of pancreatic cancer cell proliferation
In ductal adenocarcinoma of the pancreas (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 an altered extracellular niche on tumour cell growth, invasion and resistance, would therefore be a pivotal step in the quest to improve patient outcomes.
The inflammatory and fibrotic responses in PDA are the result of complex interplay between tumour and host cells. A universal feature is the generation of a dense and highly rigid stromal extracellular matrix (ECM) that, based on analyses of the adhesion-dependent control of cell phenotype in other systems, is likely to alter proliferation, migration and differentiation. Despite the importance of stromal rigidity to fate determination, a lack of methodologies to manipulate and investigate force sensing in vivo has retarded progress. These methods are now available, so it is timely to determine how stromal rigidity drives tumour progression. The focus of this programme will be the effects of rigidity on proliferation, but our findings will also provide insights into other processes, including metastasis and survival.
Three central hypotheses are being tested:
In this programme, we are building on our extensive knowledge base of integrin-mediated adhesion and the specialist methodologies that we have pioneered over the past decade to elucidate integrin function, and applying both to models of PDA. We are establishing new techniques for global analyses of the adhesion nexus in three-dimensional (3D) pancreatic organoids and defining how variations in extracellular rigidity initiate signalling at this site to influence cell cycle progression. We hope then to perturb the function of candidate molecules in organoids using knockdown and pharmacological inhibition, and employ molecular cell biology approaches to pinpoint how the sensory mechanisms vary between wild type (WT) and tumour cells. Our immediate objectives for the next five years will be:
We hope therefore to answer fundamental questions about the proteins that control normal cell behaviour, how these proteins are altered in disease, and how these changes convert normal cells into cancer 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 a cancer of massive unmet need. These findings will be relevant not only to PDA but to other highly desmoplastic cancers, such as breast, prostate and colon.