Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

SIMPLE SUMMARY: Recent progress in research on the biology of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) indicates their diverse states and plasticity, which may lead to good and bad stroma, suppressing and promoting cancer progression, respectively. The characteristics of the stroma differ spatially, even within the same tumors, based on the balance between cancer-restraining CAF and cancer-promoting CAF proliferation at the site. These heterogeneous CAFs also influence the sensitivity of PDAC to anticancer therapeutics. Further preclinical and clinical studies will advance our understanding of the roles of CAFs in disease progression and aid the development of therapeutics that modulate or ameliorate the tumor microenvironment in PDAC. ABSTRACT: A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody–drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.