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

Author:

Cyrta Joanna,Augspach Anke,De Filippo Maria Rosaria,Prandi Davide,Thienger Phillip,Benelli MatteoORCID,Cooley Victoria,Bareja Rohan,Wilkes DavidORCID,Chae Sung-Suk,Cavaliere Paola,Dephoure Noah,Uldry Anne-Christine,Lagache Sophie Braga,Roma Luca,Cohen Sandra,Jaquet Muriel,Brandt Laura P.,Alshalalfa MohammedORCID,Puca Loredana,Sboner Andrea,Feng FelixORCID,Wang Shangqian,Beltran HimishaORCID,Lotan Tamara,Spahn Martin,Kruithof-de Julio MariannaORCID,Chen YuORCID,Ballman Karla V.,Demichelis FrancescaORCID,Piscuoglio Salvatore,Rubin Mark A.ORCID

Abstract

Abstract 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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