Revealing the role of cancer-associated fibroblast senescence in prognosis and immune landscape in pancreatic cancer
Luyao Liu,
Hai Huang,
Bin Cheng,
Huaping Xie,
Wang Peng,
Haochen Cui,
Jingwen Liang,
Mengdie Cao,
Yilei Yang,
Wei Chen,
Ronghua Wang,
Yuchong Zhao
Affiliations
Luyao Liu
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Hai Huang
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Bin Cheng
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Corresponding author
Huaping Xie
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Wang Peng
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Haochen Cui
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Jingwen Liang
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Mengdie Cao
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Yilei Yang
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Wei Chen
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Ronghua Wang
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Yuchong Zhao
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Corresponding author
Summary: Cancer-associated fibroblasts (CAFs) represent a major contributor to tumor growth. Cellular senescence is a state of cell-cycle arrest characterized by a pro-inflammatory phenotype. The potential impact of CAF senescence on tumor progression and the tumor microenvironment (TME) remains to be elucidated. Here, we systematically investigated the relationship between CAF senescence and the TME of pancreatic ductal adenocarcinoma (PDAC) based on multi-omics analysis and functional experiments. CAF senescence promotes tumor progression in vitro and in vivo and contributes to the formation of immunosuppressive TME. A CAF-senescence-related risk score was developed to predict overall survival, immune landscape, and treatment sensitivity in patients with PDAC. Further experiments revealed that plasminogen activator urokinase (PLAU) derived from senescent CAFs (SCAFs) promoted PDAC progression and was involved in immunosuppression. Together, these findings suggested that CAF senescence was correlated with tumor progression, and the CAF-senescence-based machine learning model could potentially predict prognosis in patients with PDAC.
