Cancer-Associated Fibroblasts: Lessons from Pancreatic Cancer

Cancer-associated fibroblasts (CAFs) are present in all malignancies. Arguably, in none are they as prevalent as they are in pancreatic ductal adenocarcinoma (PDAC), where they often outnumber cancer cells. The origin and function of CAFs are still not completely understood, and attempts to target this cell population as a component of combination therapy have so far not succeeded. Our understanding of pancreatic CAFs is in rapid evolution. Heterogeneity of CAFs is the key concept to understand this cell population. We discuss heterogeneity of origin, with recent findings challenging the notion that CAFs uniformly derive from pancreatic stellate cells, and instead suggesting that multiple types of resident fibroblasts contribute to CAF expansion. Heterogeneity in gene expression divides CAFs in different subpopulations. Most importantly, heterogeneity in function underlies the complexity of CAFs. CAFs deposit components of the extracellular matrix, contributing to the high interstitial pressure in pancreatic cancer. CAFs serve as "feeder" cells for cancer cells by providing metabolites, thus mitigating the effect of the low-nutrient environment of PDAC. At the same time, CAFs regulate the function of the immune system, inhibiting antitumor immune responses. Understanding the functional role of different CAF populations and the drivers of each of their functional roles is key to devising new ways to target this cell population in PDAC.