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Artikel ; Online: Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

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

Cell Reports, Vol 39, Iss 1, Pp 110595- (2022)

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 ... ...

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.
Schlagwörter CP: Cancer ; Biology (General) ; QH301-705.5
Sprache Englisch
Erscheinungsdatum 2022-04-01T00:00:00Z
Verlag Elsevier
Dokumenttyp Artikel ; Online
Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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