Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach.
Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach.
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DOI：
10.3389/fcell.2021.673374
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Shen H;Chen Y;Wan Y;Liu T;Wang J;Zhang Y;Wei L;Hu Q;Xu B;Chernov M;Frangou C;Zhang J
乳腺癌干细胞(BCSCs)是一类能够自我更新并产生异质性的肿瘤细胞亚群。靶向BCSCs可能会改善治疗抵抗、肿瘤生长和转移进展。然而，其细胞特性的起源和分子机制却知之甚少。带有PDZ结合基序的转录共激活因子(TAZ)促进乳腺干/祖细胞(MASC)的扩增和维持，但也赋予分化的肿瘤细胞干细胞样特征。在这里，我们描述了通过TAZ介导的人乳腺上皮细胞的重编程来快速产生实验诱导的BCSC，从而允许直接分析BCSC的表型。具体地说，我们建立了定义明确的TAZ依赖(TAZDEP)和非依赖(TAZIND)细胞系，具有癌症干细胞(CSC)特性，如自我更新、对化疗药物的可变耐药性和肿瘤种子潜力。TAZDEP细胞与上皮向间充质转化、胚胎和MASC特征基因相关。相反，TAZIND细胞的特征是与多梳抑制复合体2(PRC2)相关的神经内分泌转分化转录程序。从机制上讲，我们认为Cyclin D1(CCND1)是TAZ驱动的肿瘤发生的关键下游效应因子。总体而言，我们的结果揭示了一个关键的TAZ-CCND1-CDK4/CDK6信号轴，提示了消除BCSCs和耐药癌细胞的新的治疗方法。
Breast cancer stem cells (BCSCs) represent a subpopulation of tumor cells that can self-renew and generate tumor heterogeneity. Targeting BCSCs may ameliorate therapy resistance, tumor growth, and metastatic progression. However, the origin and molecular mechanisms underlying their cellular properties are poorly understood. The transcriptional coactivator with PDZ-binding motif (TAZ) promotes mammary stem/progenitor cell (MaSC) expansion and maintenance but also confers stem-like traits to differentiated tumor cells. Here, we describe the rapid generation of experimentally induced BCSCs by TAZ-mediated reprogramming of human mammary epithelial cells, hence allowing for the direct analysis of BCSC phenotypes. Specifically, we establish genetically well-defined TAZ-dependent (TAZDEP) and -independent (TAZIND) cell lines with cancer stem cell (CSC) traits, such as self-renewal, variable resistance to chemotherapeutic agents, and tumor seeding potential. TAZDEP cells were associated with the epithelial to mesenchymal transition, embryonic, and MaSC signature genes. In contrast, TAZIND cells were characterized by a neuroendocrine transdifferentiation transcriptional program associated with Polycomb repressive complex 2 (PRC2). Mechanistically, we identify Cyclin D1 (CCND1) as a critical downstream effector for TAZ-driven tumorigenesis. Overall, our results reveal a critical TAZ-CCND1-CDK4/CDK6 signaling axis, suggesting novel therapeutic approaches to eliminate both BCSCs and therapy-resistant cancer cells.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
DOI：
10.1093/bioinformatics/bts251
发表时间：
2012-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Jiao X;Sherman BT;Huang da W;Stephens R;Baseler MW;Lane HC;Lempicki RA
通讯作者：
Lempicki RA
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
23.9
作者：
Brooks MD;Burness ML;Wicha MS
通讯作者：
Wicha MS
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM