POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.
POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.
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DOI：
10.1101/gad.314815.118
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发表时间：
2018-07-01
影响因子：
10.5
通讯作者：
Vakoc CR
中科院分区：
文献类型：
--
作者：
Huang YH;Klingbeil O;He XY;Wu XS;Arun G;Lu B;Somerville TDD;Milazzo JP;Wilkinson JE;Demerdash OE;Spector DL;Egeblad M;Shi J;Vakoc CR
在这里，Huang等人将聚焦于结构域的CRISPR筛选应用于小细胞肺癌，以识别由转录因子POU 2F 3的表达和依赖性定义的新分子亚型。他们还证明POU 2F 3仅在缺乏神经内分泌标志物表达的变异SCLC肿瘤中表达，这些肿瘤表达称为簇细胞的化学感受谱系的标志物。小细胞肺癌（SCLC）被广泛认为是肺神经内分泌细胞的肿瘤;然而，这种疾病的变体形式已被描述为缺乏神经内分泌特征。在这里，我们将聚焦于结构域的CRISPR筛选应用于人类癌细胞系，以鉴定转录因子（TF）POU 2F 3（POU 2类同源框3;也称为SKN-1a/OCT-11）在SCLC细胞系的子集中具有强大的依赖性。对人类SCLC标本的分析显示，POU 2F 3仅在缺乏神经内分泌标志物表达的变异SCLC肿瘤中表达，而是表达称为簇细胞的化学感受谱系的标志物。使用染色质和RNA分析实验，我们提供的证据表明，POU 2F 3是一个主调节簇细胞身份的变异形式的小细胞肺癌。此外，我们发现，大多数小细胞肺癌肿瘤可以分为三个谱系的基础上POU 2F 3，ASCL 1，或NEUROD 1的表达之一。我们的CRISPR筛选暴露了POU 2F 3表达SCLC细胞系中的其他独特依赖性，包括谱系TF SOX 9和ASCL 2以及受体酪氨酸激酶IGF 1 R（胰岛素样生长因子1受体）。这些数据揭示POU 2F 3作为细胞身份决定因素和在SCLC的簇状细胞样变体中的依赖性，这可能反映了这种疾病中先前未识别的起源细胞或转分化事件。
Here, Huang et al. applied domain-focused CRISPR screening to small cell lung cancer to identify a novel molecular subtype defined by the expression of and dependency on transcription factor POU2F3. They also demonstrate that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers, which instead express markers of a chemosensory lineage known as tuft cells. Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.
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影响因子：
8.8
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
通讯作者：
Johnson JE
影响因子：
18.4
作者：
Bhagwat AS;Vakoc CR
通讯作者：
Vakoc CR
影响因子：
64.8
作者：
Gerbe F;Sidot E;Smyth DJ;Ohmoto M;Matsumoto I;Dardalhon V;Cesses P;Garnier L;Pouzolles M;Brulin B;Bruschi M;Harcus Y;Zimmermann VS;Taylor N;Maizels RM;Jay P
通讯作者：
Jay P
影响因子：
2.5
作者：
Bezencon, C.;Fuerholz, A.;Damak, S.
通讯作者：
Damak, S.
簇细胞，味觉化学细胞，在肠道中编排寄生虫2型免疫力。
DOI：
10.1126/science.aaf1648
发表时间：
2016-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Howitt MR;Lavoie S;Michaud M;Blum AM;Tran SV;Weinstock JV;Gallini CA;Redding K;Margolskee RF;Osborne LC;Artis D;Garrett WS
通讯作者：
Garrett WS