Fibroblast Heterogeneity, Plasticity and Functions in Pancreatic Cancer

Pancreatic cancer is highly lethal, with only 1 in 10 patients surviving 5 years after diagnosis. Drug resistance is one of the main reasons of pancreatic cancer lethality and is largely caused by non-cancerous components that constitute up to 90% of the overall tumour mass and substantially contribute to the progression of the disease. Among these components, fibroblasts are the most abundant cell population and have been shown to play diverse roles, promoting drug resistance and tumour growth, but also potentially restraining cancer progression. We recently showed that pancreatic cancer fibroblasts are comprised of distinct populations, which could explain their functional diversity and emphasises the need to design selective therapies. To identify new targetable vulnerabilities, we aim to understand how pancreatic cancer cells and distinct fibroblast populations interact and affect each other. Additionally, as fibroblasts also play key roles in inflammation, we aim to determine differences and similarities of these cells across normal, inflammatory and malignant states. To address these questions, we will use mouse models and three-dimensional co-cultures of fibroblasts and pancreatic cancer cells grown as organoids. In combination with these models, we will employ genetic and pharmacologic approaches to characterise the roles, dynamic nature and heterogeneity of fibroblasts during pancreatic cancer progression and in pancreatitis, which is a pathological condition of inflammation of the pancreas and a risk factor of pancreatic cancer. In particular, we will define the mechanisms through which different genetic profiles of pancreatic cancer cells affect the heterogeneity of surrounding fibroblasts. We will also dissect fibroblast functions in both pancreatic cancer and pancreatitis. To do this, we will develop novel approaches that will enable the genetic ablation of distinct fibroblast populations in new co-cultures and mouse models. Finally, we will determine how metabolic signatures of distinct fibroblast populations are regulated and affect disease progression. Our analysis will identify in what ways fibroblast populations differentially impact pancreatic cancer progression and pancreatitis and will reveal new vulnerabilities for therapeutic intervention. The emerging understanding that some phenotypes and functions of pancreatic cancer fibroblasts are shared among different cancer types and inflammatory conditions indicates that our findings could be applied to other malignancies and diseased states.