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Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis
- Source :
- Cell Reports, Vol 39, Iss 1, Pp 110595- (2022)
- Publication Year :
- 2022
- Publisher :
- Elsevier, 2022.
-
Abstract
- Summary: 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.
- Subjects :
- CP: Cancer
Biology (General)
QH301-705.5
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 39
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Reports
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.577c4a7ae5774bfabb0ebff830f751f6
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.celrep.2022.110595