Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells.
Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells.
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不对称分裂过程中转录因子的有丝分裂极化确立了形成癌细胞的命运。
DOI：
10.1038/s41467-018-04663-1
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发表时间：
2018-06-21
影响因子：
16.6
通讯作者：
Dean DC
中科院分区：
文献类型：
--
作者：
Liu Y;Siles L;Lu X;Dean KC;Cuatrecasas M;Postigo A;Dean DC
使用K-Ras启动的肺癌模型来跟踪癌前腺瘤向腺癌的转变。在缺氧、富含TGF-β1的腺瘤内部，我们发现腺瘤细胞不对称分裂产生癌细胞，突出表现为上皮间质转化和CD 44/Zeb 1环。在这些细胞中，Zeb 1抑制Smad抑制剂Zeb 2/Sip 1，导致Pten丢失并启动Tgf-β1信号传导，驱动Yap 1的核转位。令人惊讶的是，在有丝分裂期间转录因子的核极化在胞质分裂之前建立了亲本和子代的命运，所述胞质分裂在癌前病变中产生癌细胞。肺中Zeb 1的突变或敲低阻断了腺瘤细胞产生CD 44 hi、Zeb 1 hi癌细胞。然后，CD 44/Zeb 1环通过稳定的中间致癌细胞群启动癌前细胞向癌细胞的两步转变。我们发现这些最初的癌症生成细胞独立于肿瘤中通过p53调节的现有癌细胞重编程产生的癌症干细胞。从癌前病变到癌细胞的转变凸显了肿瘤的发生。在这里，作者使用K-Ras启动的肺癌模型来记录两个连续的不对称分裂，每个分裂都由关键转录因子的有丝分裂极化驱动，这导致了初始癌细胞的产生。
A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1. Surprisingly, the nuclear polarization of transcription factors during mitosis establishes parent and daughter fates prior to cytokinesis in sequential asymmetric divisions that generate cancer cells from precancerous lesions. Mutation or knockdown of Zeb1 in the lung blocked the production of CD44hi, Zeb1hi cancer-generating cells from adenoma cells. A CD44/Zeb1 loop then initiates two-step transition of precancerous cells to cancer cells via a stable intermediate population of cancer-generating cells. We show these initial cancer-generating cells are independent of cancer stem cells generated in tumors by p53-regulated reprogramming of existing cancer cells. Transition from premalignant lesion to cancer cell highlights tumor initiation. Here, the authors use a model of K-Ras-initiated lung cancer to document two successive asymmetric divisions, each driven by mitotic polarization of key transcription factors, which lead to generation of initial cancer cells.
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影响因子：
64.8
作者：
Colaluca, Ivan N.;Tosoni, Daniela;Di Fiore, Pier Paolo
通讯作者：
Di Fiore, Pier Paolo
在致癌 BRAF 诱导的黑色素瘤小鼠模型中体内鉴定肿瘤抑制性 PTEN ceRNA。
影响因子：
64.5
作者：
Karreth FA;Tay Y;Perna D;Ala U;Tan SM;Rust AG;DeNicola G;Webster KA;Weiss D;Perez-Mancera PA;Krauthammer M;Halaban R;Provero P;Adams DJ;Tuveson DA;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
DOI：
10.1083/jcb.201310021
发表时间：
2014-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bonifacino JS
通讯作者：
Bonifacino JS
影响因子：
3.3
作者：
Gregory PA;Bracken CP;Smith E;Bert AG;Wright JA;Roslan S;Morris M;Wyatt L;Farshid G;Lim YY;Lindeman GJ;Shannon MF;Drew PA;Khew-Goodall Y;Goodall GJ
通讯作者：
Goodall GJ