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

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) a...

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Published in:Cancer cell 2023-07, Vol.41 (7), p.1345-1362.e9
Main Authors: Wang, Hanling, Li, Ni, Liu, Qiuli, Guo, Jiacheng, Pan, Qiang, Cheng, Bisheng, Xu, Junyu, Dong, Baijun, Yang, Guanjie, Yang, Bin, Wang, Xuege, Gu, Yongqiang, Zhang, Guoying, Lian, Yannan, Zhang, Wei, Zhang, Mingyu, Li, Tianyi, Zang, Yi, Tan, Minjia, Li, Qintong, Wang, Xiaoming, Yu, Zhengquan, Jiang, Jun, Huang, Hai, Qin, Jun
Format: Article
Language:English
Subjects:
Androgen Antagonists - pharmacology
Androgen Antagonists - therapeutic use
androgen deprivation treatment
cancer associated fibroblast
Castration
castration resistant prostate cancer
Cell Line, Tumor
Cellular Reprogramming
fibroblast plasticity
Humans
Male
Neoplasm Recurrence, Local - drug therapy
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - metabolism
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
SOXC Transcription Factors - genetics
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Summary: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. [Display omitted] •CRPC-related SPP1+ myCAFs resist ADT via paracrine activation of ERK signaling•AR inhibition unleashes TGF-β signaling to convert iCAFs into SPP1+ myCAFs•Targeting therapy-induced CAF conversion may enhance the effect of ADT on CRPC Wang et al. show that the polarization of cancer-associated fibroblasts (CAFs) is shaped collaboratively by the tumor microenvironment (TME) and target therapy. AR inhibition unleashes TGF-β signaling to convert inflammatory CAFs into SPP1+ myofibroblastic CAFs and targeting of CAF polarization or paracrine mechanisms may restrain castration resistant in prostate cancer.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2023.05.016