Heterogeneity in Pancreatic Cancer Fibroblasts—TGFβ as a Master Regulator?

SIMPLE SUMMARY: Pancreatic cancer has a very low survival rate and improved treatments are required. In addition to tumour cells, the disease is characterized by a significant non-tumour cell stromal component including immune cells, blood vessels and, particularly, fibroblasts whose normal role is in connective tissue and healing wounds. This stromal environment can affect tumour progression and play a role in response to therapy. Whilst there is relatively good understanding of the deregulated signalling in the tumour cells, less attention has been paid to the stroma until recently. It is now apparent that there is significant variation within and between the stroma in different tumours, in particular, between fibroblast populations. TGFβ is a growth factor that can play a role in cancer cells, but also in shaping the tumour stroma. Here we review recent developments in our understanding of the fibroblast populations within PDAC with a focus on TGFβ signalling. ABSTRACT: Pancreatic ductal adenocarcinoma is an aggressive disease for which there are very few available therapies. It is notable for its high degree of tumour complexity, with the tumour microenvironment often accounting for the majority of the tumour volume. Until recently, the biology of the stroma was poorly understood, particularly in terms of heterogeneity. Recent research, however, has shed light on the intricacy of signalling within the stroma and particularly the molecular and functional heterogeneity of the cancer associated fibroblasts. In this review, we summarise the recent improvements in our understanding of the different fibroblast populations within PDAC, with a focus on the role TGFβ plays to dictate their formation and function. These studies have highlighted some of the reasons for the failure of trials targeting the tumour stroma, however, there are still considerable gaps in our knowledge, and more work is needed to make effective fibroblast targeting a reality in the clinic.