Lineage plasticity causes therapeutic resistance; however, it remains unclear how the fate conversion and phenotype switching of cancer-associated fibroblasts (CAFs) are implicated in disease relapse. Here, we show that androgen deprivation therapy (ADT)-induced SPP1+ myofibroblastic CAFs (myCAFs) are critical stromal constituents that drive the development of castration-resistant prostate cancer (CRPC). Our results reveal that SPP1+ myCAFs arise from the inflammatory CAFs in hormone-sensitive PCa; therefore, they represent two functional states of an otherwise ontogenically identical cell type. Antiandrogen treatment unleashes TGF-β signaling, resulting in SOX4-SWI/SNF-dependent CAF phenotype switching. SPP1+ myCAFs in turn render PCa refractory to ADT via an SPP1-ERK paracrine mechanism. Importantly, these sub-myCAFs are associated with inferior therapeutic outcomes, providing the rationale for inhibiting polarization or paracrine mechanisms to circumvent castration resistance. Collectively, our results highlight that therapy-induced phenotypic switching of CAFs is coupled with disease progression and that targeting this stromal component may restrain CRPC.
Cancer cell. 2023 Jun 22 [Epub]
Hanling Wang, Ni Li, Qiuli Liu, Jiacheng Guo, Qiang Pan, Bisheng Cheng, Junyu Xu, Baijun Dong, Guanjie Yang, Bin Yang, Xuege Wang, Yongqiang Gu, Guoying Zhang, Yannan Lian, Wei Zhang, Mingyu Zhang, Tianyi Li, Yi Zang, Minjia Tan, Qintong Li, Xiaoming Wang, Zhengquan Yu, Jun Jiang, Hai Huang, Jun Qin
CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China., Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China., Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China., State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China., Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai 200072, China., Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Sichuan University, 20 Renmin South Road, Chengdu 610041, China., Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China., State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China., Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: ., Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: ., CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: .