Department for BioMedical Research, University of Bern, 3008, Bern, Switzerland.
The Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
Nat Commun. 2020 Nov 3;11(1):5549. doi: 10.1038/s41467-020-19328-1.
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.
晚期前列腺癌最初对激素治疗有反应，但最终会产生抗药性，需要更有效的治疗方法。大约 10-20%的患者会出现一种耐药机制，即谱系可塑性，表现为部分或完全的小细胞或神经内分泌前列腺癌（NEPC）表型。在这里，我们研究了哺乳动物 SWI/SNF（mSWI/SNF）染色质重塑复合物在 NEPC 中的作用。我们使用大型患者数据集、患者来源的类器官和癌细胞系，鉴定出在 NEPC 中失调的 mSWI/SNF 亚基，并证明 SMARCA4（BRG1）过表达与侵袭性疾病相关。我们还表明，与前列腺腺癌相比，SWI/SNF 复合物在 NEPC 中与不同谱系特异性因子相互作用。这些数据表明 mSWI/SNF 复合物在治疗相关谱系可塑性中发挥作用，这对于其他实体瘤也可能相关。
