Multi-omics analysis reveals the chemoresistance mechanism of proliferating tissue-resident macrophages in PDAC via metabolic adaptation
Junlei Zhang,
Jinyuan Song,
Shima Tang,
Yaxing Zhao,
Lin Wang,
Yandong Luo,
Jianghui Tang,
Yongtao Ji,
Xun Wang,
Taohong Li,
Hui Zhang,
Wei Shao,
Jianpeng Sheng,
Tingbo Liang,
Xueli Bai
Affiliations
Junlei Zhang
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Jinyuan Song
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Shima Tang
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China
Yaxing Zhao
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Lin Wang
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Yandong Luo
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Jianghui Tang
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Yongtao Ji
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Xun Wang
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Taohong Li
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Hui Zhang
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China
Wei Shao
College of Computer Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing 210000, China; Corresponding author
Jianpeng Sheng
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China; Corresponding author
Tingbo Liang
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China; Corresponding author
Xueli Bai
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310002, China; Corresponding author
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically demonstrates resistance to chemotherapy. Tumor-associated macrophages (TAMs) are essential in tumor microenvironment (TME) regulation, including promoting chemoresistance. However, the specific TAM subset and mechanisms behind this promotion remain unclear. We employ multi-omics strategies, including single-cell RNA sequencing (scRNA-seq), transcriptomics, multicolor immunohistochemistry (mIHC), flow cytometry, and metabolomics, to analyze chemotherapy-treated samples from both humans and mice. We identify four major TAM subsets within PDAC, among which proliferating resident macrophages (proliferating rMφs) are strongly associated with poor clinical outcomes. These macrophages are able to survive chemotherapy by producing more deoxycytidine (dC) and fewer dC kinases (dCKs) to decrease the absorption of gemcitabine. Moreover, proliferating rMφs promote fibrosis and immunosuppression in PDAC. Eliminating them in the transgenic mouse model alleviates fibrosis and immunosuppression, thereby re-sensitizing PDAC to chemotherapy. Consequently, targeting proliferating rMφs may become a potential treatment strategy for PDAC to enhance chemotherapy.
