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

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.

Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

“…Many SWI/SNF subunits have been shown carry inactivating mutations in different cancers thus supporting the role of this chromatin remodeling complex as regulator of tumorigenesis [106]. Recently, based on a genome-wide study by Cyrta et al, on the role of SWI/SNF in NEPC, a potential tumor-promoting function of this chromatin remodeling complex was shown [107]. In particular, increased expression of the SMARCA4 (Brg1) subunit was associated with the aggressive neuroendocrine phenotype of prostate cancer, marked by increased NE marker expression and shorter overall survival [107].…”

“…Recently, based on a genome-wide study by Cyrta et al, on the role of SWI/SNF in NEPC, a potential tumor-promoting function of this chromatin remodeling complex was shown [107]. In particular, increased expression of the SMARCA4 (Brg1) subunit was associated with the aggressive neuroendocrine phenotype of prostate cancer, marked by increased NE marker expression and shorter overall survival [107]. Furthermore, SMARCA4 was shown to interact with several factors specific to neural differentiation, including the transcription factor NKX2.1 (also known as TTF-1) and the growth factor VGF, indicating the involvement of SMARCA4 and thus the SWI/SNF complex in NEPC-related neurogenesis [107].…”

Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression.

“…For the assessment of CD11c protein expression in primary prostate cancer and the correlation with PSArecurrence patients were selected from two previously characterized tissue microarrays cohorts constructed in Zurich and Bern [75][76][77] . Due to tissue loss, a common problem associated with TMA technology, a total of 482 high-quality tissue samples of primary tumor remained after sectioning (n = 272 from Zurich and n = 210 from Bern).…”

Single-cell ATAC and RNA sequencing reveal pre-existing and persistent subpopulations of cells associated with relapse of prostate cancer

“…Only a few studies to date have used single-cell sequencing technology on human PC tumor specimens (Chen et al, 2021;Cyrta et al, 2020;Dong et al, 2020;Karthaus et al, 2020;Ma et al, 2020b;Song et al) . Although these approaches characterize features of individual tumors, they do not allow for elucidation of the temporal sequence of events occurring during the evolution of drug resistance.…”

“…Only a few studies to date have used single-cell sequencing technology on human PC tumor specimens (Chen et al, 2021; Cyrta et al, 2020; Dong et al, 2020; He et al. ; Karthaus et al, 2020; Ma et al, 2020b; Song et al.).…”