美国桑德拉和爱德华迈耶癌症中心Ekta Khurana和美国纪念斯隆凯特琳癌症中心Yu Chen研究组，合作利用染色质谱对去势抵抗性前列腺癌 (CRPC)进行分类，揭示治疗靶点。该项研究成果发表在2022年5月27日出版的《科学》上。
他们使用 ATAC-seq（转座酶可及染色质测序分析）、RNA-seq 和 DNA 测序来研究 22 个类器官、6 个源自患者的异种移植物和 12 个细胞系。他们确定了充分表征的雄激素受体 (AR)依赖性和神经内分泌亚型，以及两个 AR 阴性/低组：Wnt 依赖性亚型和由激活蛋白-1 (AP-1) 驱动的干细胞样 (SCL) 亚型) 转录因子。他们使用转录组特征对 366 名患者进行分类，这表明 SCL 是继 AR 依赖性CRPC之后第二常见的 CRPC 亚型。
他们的数据表明，AP-1 与 YAP/TAZ 和 TEAD 蛋白相互作用，以维持该组亚型特异性染色质可及性和转录组学景观。总之，这种分子分类揭示了药物靶点，并可能指导治疗决策。
据介绍，在CRPC中，AR的丧失依赖地导致临床侵袭性肿瘤，几乎没有治疗选择。
附：英文原文
Title: Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets
Author: Fanying Tang, Duo Xu, Shangqian Wang, Chen Khuan Wong, Alexander Martinez-Fundichely, Cindy J. Lee, Sandra Cohen, Jane Park, Corinne E. Hill, Kenneth Eng, Rohan Bareja, Teng Han, Eric Minwei Liu, Ann Palladino, Wei Di, Dong Gao, Wassim Abida, Shaham Beg, Loredana Puca, Maximiliano Meneses, Elisa de Stanchina, Michael F. Berger, Anuradha Gopalan, Lukas E. Dow, Juan Miguel Mosquera, Himisha Beltran, Cora N. Sternberg, Ping Chi, Howard I. Scher, Andrea Sboner, Yu Chen, Ekta Khurana
Issue&Volume: 2022-05-27
Abstract: In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell–like (SCL) subtype driven by activator protein–1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.
DOI: abe1505
Source: https://www.science.org/doi/10.1126/science.abe1505