{"doi":"10.1016/j.celrep.2022.110595","title":"Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis","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.","journal":"Cell Reports","year":2022,"id":236376,"datarank":1.7490954397416454,"base_score":4.248495242049359,"endowment":4.248495242049359,"self_citation_contribution":0.637274286307404,"citation_network_contribution":1.1118211534342413,"self_endowment_contribution":0.637274286307404,"citer_contribution":1.1118211534342413,"corpus_percentile":null,"corpus_rank":null,"citation_count":69,"citer_count":63,"citers_with_citation_signal":48,"citers_with_endowment":48,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT01946165"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":286530,"name":"Yan Wang","orcid":"0000-0002-1743-6383","position":1,"is_corresponding":false},{"id":823781,"name":"Josué Curto","orcid":null,"position":2,"is_corresponding":false},{"id":821263,"name":"Sreeharsha Gurrapu","orcid":"0000-0003-2195-2767","position":3,"is_corresponding":false},{"id":821876,"name":"Sara Laudato","orcid":null,"position":4,"is_corresponding":false},{"id":823532,"name":"Alekya Rumandla","orcid":"0000-0002-3940-5027","position":5,"is_corresponding":false},{"id":368441,"name":"Goutam Chakraborty","orcid":"0000-0002-4387-2621","position":6,"is_corresponding":false},{"id":823533,"name":"Xiaobo Wang","orcid":"0000-0003-0397-919X","position":7,"is_corresponding":false},{"id":680436,"name":"Hong Chen","orcid":"0000-0001-8054-7417","position":8,"is_corresponding":false},{"id":397264,"name":"Yan Jiang","orcid":"0000-0002-1945-4200","position":9,"is_corresponding":false},{"id":822630,"name":"Dhiraj Kumar","orcid":"0000-0002-6085-5911","position":10,"is_corresponding":false},{"id":821264,"name":"Emily G. 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