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Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

Authors
 Hyunho Han  ;  Yan Wang  ;  Josue Curto  ;  Sreeharsha Gurrapu  ;  Sara Laudato  ;  Alekya Rumandla  ;  Goutam Chakraborty  ;  Xiaobo Wang  ;  Hong Chen  ;  Yan Jiang  ;  Dhiraj Kumar  ;  Emily G Caggiano  ;  Monica Capogiri  ;  Boyu Zhang  ;  Yan Ji  ;  Sankar N Maity  ;  Min Hu  ;  Shanshan Bai  ;  Ana M Aparicio  ;  Eleni Efstathiou  ;  Christopher J Logothetis  ;  Nicholas Navin  ;  Nora M Navone  ;  Yu Chen  ;  Filippo G Giancotti 
Citation
 CELL REPORTS, Vol.39(1) : 110595, 2022-04 
Journal Title
CELL REPORTS
Issue Date
2022-04
MeSH
Animals ; Antineoplastic Agents* / pharmacology ; Benzamides ; Carcinoma, Neuroendocrine ; Cell Line, Tumor ; Cell Plasticity / drug effects ; Cell Plasticity / physiology ; Drug Resistance, Neoplasm ; Humans ; Male ; Mice ; Neoplastic Stem Cells / drug effects ; Neoplastic Stem Cells / metabolism ; Nitriles ; Phenylthiohydantoin ; Prostatic Neoplasms, Castration-Resistant* / drug therapy ; Prostatic Neoplasms, Castration-Resistant* / genetics ; Prostatic Neoplasms, Castration-Resistant* / metabolism ; Receptors, Androgen / drug effects ; Receptors, Androgen / metabolism ; Signal Transduction* ; Tumor Microenvironment / drug effects ; Tumor Microenvironment / physiology
Keywords
BMP-SMAD signaling ; CP: Cancer ; TP53 ; androgen receptor signaling ; prostate cancer
Abstract
Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
Files in This Item:
T202202207.pdf Download
DOI
10.1016/j.celrep.2022.110595
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Han, Hyun Ho(한현호) ORCID logo https://orcid.org/0000-0002-6268-0860
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/189314
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