Assessment of stromal SCD-induced drug resistance of PDAC using 3D-printed zPDX model chips
Chuntao Wu,
Beiyuan Hu,
Lei Wang,
Xia Wu,
Haitao Gu,
Hanguang Dong,
Jiuliang Yan,
Zihao Qi,
Qi Zhang,
Huan Chen,
Bo Yu,
Sheng Hu,
Yu Qian,
Shuang Dong,
Qiang Li,
Xu Wang,
Jiang Long
Affiliations
Chuntao Wu
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Beiyuan Hu
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Lei Wang
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Xia Wu
Department of General Practice, Jing’an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing’an Branch), Shanghai 200040, China
Haitao Gu
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Hanguang Dong
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Jiuliang Yan
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Zihao Qi
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Qi Zhang
Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect, Institute of Pediatrics, Children’s Hospital of Fudan University, Shanghai 201102, China
Huan Chen
National Human Genetic Resources Sharing Service Platform (2005DKA21300), Fudan University Shanghai Cancer Center, Shanghai 200032, China
Bo Yu
Department of Pharmacy, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200336, China
Sheng Hu
Department of Thoracic Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
Yu Qian
Department of Thoracic Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
Shuang Dong
Department of Thoracic Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
Qiang Li
Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect, Institute of Pediatrics, Children’s Hospital of Fudan University, Shanghai 201102, China; Corresponding author
Xu Wang
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Corresponding author
Jiang Long
Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; Corresponding author
Summary: Lipid metabolism is extensively reprogrammed in pancreatic ductal adenocarcinoma (PDAC). Stearoyl-coenzyme A desaturase (SCD) is a critical lipid regulator that was unexplored in PDAC. Here, we characterized the existence of cancer-associated fibroblasts (CAFs) with high SCD expression, and revealed them as an unfavorable prognostic factor. Therefore, primary CAFs and pancreatic cancer cells were harvested and genetically labeled. The mixture of CAFs and cancer cells were co-injected into scd−/−; prkdc−/−, or hIGF1/INS-expressing zebrafish to generate patient-derived xenograft models (zPDX). The models were aligned in 3D-printed chips for semi-automatic drug administration and high-throughput scanning. The results showed that chaperoning of the SCD-high CAFs significantly improved the drug resistance of pancreatic cancer cells against gemcitabine and cisplatin, while the administration of SCD inhibitors neutralized the protective effect. Our studies revealed the prognostic and therapeutic value of stromal SCD in PDAC, and proposed the application of zPDX model chips for drug testing.
