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

Joanna Cyrta(University of Bern), Anke Augspach(University of Bern), Maria Rosaria De Filippo(University of Bern), Davide Prandi(University of Trento), Phillip Thienger(University of Bern), Matteo Benelli(University of Trento), Victoria Cooley(Cornell University), Rohan Bareja(Cornell University), David Wilkes(Cornell University), Sung-Suk Chae(Cornell University), Paola Cavaliere(Cornell University), Noah Dephoure(Cornell University), Anne‐Christine Uldry(University of Bern), Sophie Braga Lagache(University of Bern), Luca Roma(University of Basel), Sandra Cohen(Cornell University), Muriel Jaquet(University of Bern), Laura P. Brandt(University of Bern), Mohammed Alshalalfa(UCSF Helen Diller Family Comprehensive Cancer Center), Loredana Puca(Cornell University), Andrea Sboner(Prince Sattam Bin Abdulaziz University), Felix Y. Feng(University of Bern), Shangqian Wang(Memorial Sloan Kettering Cancer Center), Himisha Beltran(Cornell University), Tamara Lotan(Johns Hopkins University), Martin Spahn(Essen University Hospital), Marianna Kruithof‐de Julio(University of Bern), Yu Chen(Cornell University), Karla V. Ballman(Cornell University), Francesca Demichelis(University of Trento), Salvatore Piscuoglio(University of Basel), Mark A. Rubin(University of Bern)
Nature Communications
November 3, 2020
10.1038/s41467-020-19328-1
Cited by 147Open Access
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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.

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