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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-19328-1

2041-1723

Joanna Cyrta, Anke Augspach, Maria Rosaria De Filippo, Davide Prandi, Phillip Thienger, Matteo Benelli, Victoria Cooley, Rohan Bareja, David Wilkes, Sung-Suk Chae, Paola Cavaliere, Noah Dephoure, Anne-Christine Uldry, Sophie Braga Lagache, Luca Roma, Sandra Cohen, Muriel Jaquet, Laura P. Brandt, Mohammed Alshalalfa, Loredana Puca, Andrea Sboner, Felix Y. Feng, Shangqian Wang, Himisha Beltran, Tamara Lotan, Martin Spahn, Marianna Kruithof‐de Julio, Yu Chen, Karla V. Ballman, Francesca Demichelis, Salvatore Piscuoglio, Mark A. Rubin,

Mechanisms of cancer metastasis

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.