Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer

  • Cancer Cell. 2023 Jun 11;S1535-6108(23)00183-6. doi: 10.1016/j.ccell.2023.05.016.
Hanling Wang  1 ,  Ni Li  1 ,  Qiuli Liu  2 ,  Jiacheng Guo  1 ,  Qiang Pan  1 ,  Bisheng Cheng  3 ,  Junyu Xu  4 ,  Baijun Dong  5 ,  Guanjie Yang  6 ,  Bin Yang  6 ,  Xuege Wang  1 ,  Yongqiang Gu  1 ,  Guoying Zhang  1 ,  Yannan Lian  1 ,  Wei Zhang  1 ,  Mingyu Zhang  1 ,  Tianyi Li  1 ,  Yi Zang  1 ,  Minjia Tan  4 ,  Qintong Li  7 ,  Xiaoming Wang  8 ,  Zhengquan Yu  9 ,  Jun Jiang  10 ,  Hai Huang  11 ,  Jun Qin  12
Affiliations
  • 1. 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.
  • 2. Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 3. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 6. Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai 200072, China.
  • 7. Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Sichuan University, 20 Renmin South Road, Chengdu 610041, China.
  • 8. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China.
  • 9. State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
  • 10. Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: [email protected].
  • 11. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: [email protected].
  • 12. 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: [email protected].
PMID: 37352863 DOI: 10.1016/j.ccell.2023.05.016
Abstract

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.

Keywords
androgen deprivation treatment; cancer associated fibroblast; castration resistant prostate cancer; fibroblast plasticity.
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