Cellular origin of normal pancreatic fibroblasts and cancer-associated fibroblasts (CAFs)

A type of cell that plays a key role in pancreatic cancer can trace its origin back to a structure that forms during embryonic development, new research shows. This new data, published recently in Nature Communications, is the first to show the cellular origin of normal pancreatic fibroblasts and cancer-associated fibroblasts (CAFs) that influence tumor progression. The research findings open the door for new therapeutic targets for pancreatic cancer, which remains challenging to treat.  

Pancreatic ductal adenocarcinoma, which accounts for more than 90% of pancreatic cancers, is one of the deadliest types of cancer. Despite accounting for only about 3% of all cancers in the U.S., it causes about 7% of cancer deaths. According to the American Cancer Society, more than 50,000 people are expected to die from pancreatic cancer in the U.S. in 2023.  

“More effective therapeutics are urgently needed for patients with pancreatic cancer,” said the lead author of the publication. “Most patients die within five years of their diagnosis. We aimed to learn the basic biology of pancreatic cancer so we can provide information to lead to more effective treatments.” 

While pancreatic cancer is driven by tumor cells, fibroblasts are cells that control the microenvironment around the tumor. “A healthy pancreas contains very few fibroblasts. However, there is a drastic increase in the number of fibroblasts when a tumor forms in the pancreas and fibroblasts play important and complex roles in how the disease progresses,” the lead said.  

Targeting CAFs holds exciting potential for therapeutic benefits. The lead said that knowing the basic biology of this cell type is the initial step. Many studies show that there may be multiple types of CAFs, which may play different roles in either promoting or prohibiting cancer progression. “Understanding the specific factors within each CAF subtype will help us direct future therapeutic design. Ideally, we want to be able to promote the CAFs that reduce cancer cell growth and inhibit the tumor-promoting CAFs,” said the author. 

They first focused on determining the origin of these cells. “Other researchers have proposed that the different CAF subtypes found in pancreatic cancers come from different origins, meaning that they develop from different cells,” the lead said. The potential CAF origins include pancreatic epithelial cells, the bone marrow and pancreatic resident fibroblasts – fibroblasts in the normal adult pancreas. They formally tested that hypothesis by engineering elegant mouse genetic models of pancreatic cancer. 

“What we found was a bit surprising. The bone marrow and epithelial cells only had minimal contributions to CAFs. We found that both resident fibroblasts and CAFs came from the splanchnic mesenchyme, a layer of cells in an embryo during early development,” the author said. This new finding about the fetal origin of the pancreatic fibroblasts suggested that the different CAF subtypes found in pancreatic cancer are likely caused by the tumor microenvironment driving the diversification of the fibroblasts.  

Next, the authors studied whether the CAFs also had the same gene signature of their fetal origin. Figuring out the gene signature similarities could offer novel insights into CAF heterogeneity and the complex roles CAFs play in pancreatic cancer progression.  

The gene signature studies revealed two distinct groups of genes. The normal pancreatic fibroblasts shared a group of genes with the splanchnic mesenchyme that is potentially important for normal organ maintenance. The CAFs shared a different group of genes, which potentially play a role in promoting rapid cell multiplication. This observation was seen in their mouse models and human pancreatic tissues, suggesting that some fetal development programs are turned back on in the fibroblast lineage during tumor development.  

“During tumor development, the splanchnic-derived fibroblasts quickly multiply and become a large portion of the pancreatic cancer tissue mass. The importance of the fetal development programs in the CAFs is a really exciting direction and has not been explored before this study,” said the lead author.  

The results give a new direction for pancreatic cancer researchers by providing valuable insights into fibroblast biology during pancreatic cancer progression. Han and Ostrowski’s laboratory are diving into more studies to understand the functional importance of the fetal development program in CAFs, which will be translated into better-targeted therapeutics in the future.