{"doi":"10.1101/2021.04.14.439569","title":"Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer","abstract":"Summary Unsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222429,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":557889,"name":"Yan Wang","orcid":"0000-0001-5624-6745","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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