Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis Journal Article
| Authors: | Han, H.; Wang, Y.; Curto, J.; Gurrapu, S.; Laudato, S.; Rumandla, A.; Chakraborty, G.; Wang, X.; Chen, H.; Jiang, Y.; Kumar, D.; Caggiano, E. G.; Capogiri, M.; Zhang, B.; Ji, Y.; Maity, S. N.; Hu, M.; Bai, S.; Aparicio, A. M.; Efstathiou, E.; Logothetis, C. J.; Navin, N.; Navone, N. M.; Chen, Y.; Giancotti, F. G. |
| Article 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. © 2022 The Authors |
| Keywords: | signal transduction; human tissue; human cell; drug efficacy; nonhuman; mouse; cell cycle; mesenchyme cell; metastasis; bone morphogenetic protein; epidermal growth factor receptor 2; animal experiment; animal model; antineoplastic activity; protein p53; cell lineage; prostate cancer; epithelium cell; androgen receptor; gene silencing; receptor blocking; epidermal growth factor receptor 3; bioinformatics; nuclear reprogramming; neratinib; castration resistant prostate cancer; cell dedifferentiation; neu differentiation factor; mammalian target of rapamycin complex 1; tp53; tp53 gene; cell plasticity; enzalutamide; human; male; article; neuroendocrine prostate cancer; androgen receptor signaling; bmp-smad signaling; cp: cancer; androgen receptor positive prostate cancer; mesenchymal and stem like prostate cancer |
| Journal Title: | Cell Reports |
| Volume: | 39 |
| Issue: | 1 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2022-04-05 |
| Start Page: | 110595 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2022.110595 |
| PUBMED: | 35385726 |
| PROVIDER: | scopus |
| PMCID: | PMC9414743 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
