Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

• Published in: Nature communications Vol. 11; no. 1; pp. 5549 - 16
• Main Authors: Cyrta, Joanna, Augspach, Anke, De Filippo, Maria Rosaria, Prandi, Davide, Thienger, Phillip, Benelli, Matteo, Cooley, Victoria, Bareja, Rohan, Wilkes, David, Chae, Sung-Suk, Cavaliere, Paola, Dephoure, Noah, Uldry, Anne-Christine, Lagache, Sophie Braga, Roma, Luca, Cohen, Sandra, Jaquet, Muriel, Brandt, Laura P., Alshalalfa, Mohammed, Puca, Loredana, Sboner, Andrea, Feng, Felix, Wang, Shangqian, Beltran, Himisha, Lotan, Tamara, Spahn, Martin, Kruithof-de Julio, Marianna, Chen, Yu, Ballman, Karla V., Demichelis, Francesca, Piscuoglio, Salvatore, Rubin, Mark A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 45; 631/67/589/466; 631/67/68/2486; Adenocarcinoma; BRG1 protein; Chromatin remodeling; Data points; Deprivation; Deregulation; Humanities and Social Sciences; multidisciplinary; Organoids; Phenotypes; Plastic properties; Plasticity; Prostate cancer; Science; Science (multidisciplinary); Solid tumors; Tumor cell lines
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19328-1

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10–20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors. The differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (CRPC-NE) is a mechanism of resistance to androgen deprivation therapy. Here the authors show that SWI/SNF chromatin-remodeling complex is deregulated in CRPC-NE and that the complex interacts with different lineage specific factors throughout prostate cancer transdifferentiation.