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

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

doi:10.1038/s41467-020-19328-1

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.

Highlights

Advanced prostate cancer initially responds to hormonal treatment, but becomes resistant and requires more potent therapies
To define somatic mutation frequencies of genes encoding SWI/SNF subunits across the entire spectrum of Prostate cancer (PCa), we conducted a comprehensive analysis of whole exome sequencing (WES) data from 600 PCa patients representing a wide range of the disease spectrum, including 56 castration-resistant prostate cancer (CRPC)-NE cases (Fig. 1a, Supplementary Data 1, Supplementary Data 2, Supplementary Data 3)
Expression levels of BRD7 were significantly lower in CRPC-NE compared to CRPC-Adeno, but not in CRPC-NE compared to localized PCa

Summary

Introduction

Advanced prostate cancer initially responds to hormonal treatment, but becomes resistant and requires more potent therapies. We 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 be relevant for other solid tumors. Mammalian SWI/SNF complexes, known as Brg/Brahmaassociated factor (BAF) complexes, are a heterogeneous family of ATP-dependent chromatin remodeling complexes composed of about 11–15 protein subunits and generally considered as positive mediators of chromatin accessibility[16] These complexes are evolutionarily conserved in eukaryotes and required for normal embryonic development[16,17]. We provide evidence that SWI/SNF interacts with different lineage-specific partners throughout PCa transdifferentiation These findings suggest that specialized SWI/SNF complexes are associated with PCa disease progression and may play a role in therapy resistance

Methods

Results

Conclusion