Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis
Hyun Ho Han, Yan Wang, Josué 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 E. Navin, Nora M. Navone, Yu Chen, Filippo G. Giancotti
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.