Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

SIMPLE SUMMARY: This review summarises the current understanding of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to discuss recent advances in CAF biology, the various roles of CAFs, and different CAF subtypes. We will also examine the evolution of CAFs as tumours progress, and the relationship between CAFs and other cell types within PDAC tumours. Finally, we will provide an update on the potential for therapeutic targeting of certain aspects of CAF biology, and discuss future directions for this exciting and rapidly-progressing field. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.