Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.
Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.
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将前列腺癌细胞 AR 异质性与不同的去势和恩杂鲁胺反应联系起来。
DOI：
10.1038/s41467-018-06067-7
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发表时间：
2018-09-06
影响因子：
16.6
通讯作者：
Tang DG
中科院分区：
文献类型：
--
作者：
Li Q;Deng Q;Chao HP;Liu X;Lu Y;Lin K;Liu B;Tang GW;Zhang D;Tracz A;Jeter C;Rycaj K;Calhoun-Davis T;Huang J;Rubin MA;Beltran H;Shen J;Chatta G;Puzanov I;Mohler JL;Wang J;Zhao R;Kirk J;Chen X;Tang DG
雄激素受体(AR)在前列腺癌(PCa)中的表达具有异质性，但AR异质性的功能意义尚不清楚。筛选89例患者的抗去势PCa核心和整装切片，发现AR有3种表达模式：核型(nuc-AR)、核浆混合型(nuc/cyto-AR)和低表达/不表达(AR−/lo)。异种移植模型显示AR+CRPC对苯扎鲁胺敏感，而AR−/lo CRPC耐药。基因组编辑衍生的AR+和AR-基因敲除的LNCaP细胞克隆显示出不同的生物学和致瘤特性，以及对苯扎鲁胺的对比反应。核糖核酸序列和生化分析，再加上实验性的联合治疗，将bcl2确定为关键的治疗靶点，并为AR+/HI和AR−/lo CRPC提供概念验证治疗方案。我们的研究将AR表达的异质性与不同的去势/苯扎鲁胺反应联系起来，这对于理解前列腺癌对AR靶向治疗的细胞基础以及促进针对AR−/Lo PCa细胞/克隆的新疗法的开发具有重要意义。雄激素受体(AR)在前列腺癌中异质性表达的功能意义尚不清楚。在这里，作者表明AR表达的异质性与不同的去势/苯扎鲁胺反应相关，并确认bcl2是去势抵抗前列腺癌的潜在治疗靶点。
Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR−/lo). Xenograft modeling demonstrates that AR+ CRPC is enzalutamide-sensitive but AR−/lo CRPC is resistant. Genome editing-derived AR+ and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR+/hi and AR−/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR−/lo PCa cells/clones. The functional significance of the observed heterogeneity of androgen receptor (AR) expression in prostate cancer is unknown. Here the authors show AR expression heterogeneity is associated with distinct castration/enzalutamide responses and identify BCL-2 as a potential therapeutic target in castration-resistant prostate cancer.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C
影响因子：
7.3
作者：
DEWINTER, JAR;TRAPMAN, J;VANDERKWAST, TH
通讯作者：
VANDERKWAST, TH