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

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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

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.