Pancreatic cancer involves the interaction between tumor cells and their neighboring cells—fibroblasts. However, these interactions are still poorly understood in the scientific community. A new study conducted in collaboration with the Medical University of South Carolina Hollings Cancer Center (MUSC) sheds light on the basic biology of the disease, revealing that pancreatic cancer-associated fibroblasts (CAFs) originate from a particular tissue type during fetal development.
“We discovered the heterogeneity of CAFs is unlikely to arise from different tissues, but instead stems from a certain embryo region called splanchnic mesenchyme. This finding advances our understanding of pancreatic morphogenesis and tumorigenesis, and provides information that may lead to more effective cancer treatments,” said co-author Kun Fang, postdoctoral fellow in MCW’s Department of Biostatistics.
Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90 percent of all pancreatic cancer cases. The disease is notoriously deadly because early symptoms can be difficult to detect until the cancer has spread to other areas of the body. The American Cancer Society projects that pancreatic cancer will be the second leading cause of cancer death by 2030.
The study, which was published in published in Nature Communications, is the first to reveal the cellular origin of normal pancreatic fibroblasts and CAFs, which play an important and complex role in disease progression. Prior research has suggested that different kinds of fibroblasts in the pancreas came from different origins, potentially from bone marrow and epithelial cells. The team conducted lineage tracing experiments using a genetically engineered mouse model of PDAC to discover that bone marrow and epithelium contribute minimally to pancreatic CAFs.
“We were surprised to learn different kinds of fibroblasts in the pancreas all come from one tissue, then diverge into different kinds. These findings helped to establish a trajectory of cells from fetal development to normal adult pancreas to pancreatic cancer. Furthermore, there is a series of factors that are turned either up or down along this trajectory,” said Lu Han, PhD, Postdoctoral Fellow, Department of Biochemistry and Molecular Biology, MUSC.
Dr. Han, first author of the study and mentee of Cancer Center Director Gustavo Leone, PhD, explained that the research also led to the development of relevant preclinical models of pancreatic cancer where both tumor cells and fibroblasts can be targeted separately or simultaneously.
“Our next steps are to follow up on the observation that a series of factors go either up or down during the trajectory of becoming normal fibroblasts or CAFs in the pancreas. We are currently determining how these trends are regulated and the roles these factors play in CAFs to influence pancreatic cancer progression,” said Dr. Han.
Over the last year, MCW’s LaBahn Pancreatic Cancer Program has published 22 studies, served more than 200 patients, and managed six active clinical trials. The program is recognized as one of seven in the National Institutes of Health PDAC Stromal Reprogramming Consortium. Dr. Leone hopes ongoing collaboration with other leading cancer centers will help our program maintain momentum so researchers can continue making significant progress in the battle against pancreatic cancer.
“Science is the driver of innovation and knowledge that can change how we define, diagnose, and treat disease. Working closely with partners that share our vision of advancing health through science will help to accelerate discoveries and drive development of new therapeutic targets for pancreatic cancer,” said Dr. Leone.