Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis
Qin, Zhen1,2; Sun, Honghua1,2; Yue, Meiting1,2; Pan, Xinwen1,3; Chen, Liang4; Feng, Xinhua5; Yan, Xiumin1,2; Zhu, Xueliang1,2,3,6; Ji, Hongbin1,2,3
2021-05-11
发表期刊CELL DISCOVERY
EISSN2056-5968
卷号7期号:1
DOI10.1038/s41421-021-00270-5
摘要EML4-ALK fusion, observed in about 3%-7% of human lung adenocarcinoma, is one of the most important oncogenic drivers in initiating lung tumorigenesis. However, it still remains largely unknown about how EML4-ALK fusion exactly fires downstream signaling and drives lung cancer formation. We here find that EML4-ALK variant 1 (exon 1-13 of EML4 fused to exon 20-29 of ALK) forms condensates via phase separation in the cytoplasm of various human cancer cell lines. Using two genetically engineered mouse models (GEMMs), we find that EML4-ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4-ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4-ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4-ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4-ALK fusion.
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收录类别SCIE
语种英语
WOS研究方向Cell Biology
WOS类目Cell Biology
WOS记录号WOS:000649370700001
出版者SPRINGERNATURE
原始文献类型Article
引用统计
文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126655
专题生命科学与技术学院_博士生
生命科学与技术学院_特聘教授组_季红斌组
生命科学与技术学院_特聘教授组_朱学良组
通讯作者Yan, Xiumin; Zhu, Xueliang; Ji, Hongbin
作者单位1.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, Shanghai, Peoples R China;
2.Univ Chinese Acad Sci, Beijing, Peoples R China;
3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China;
4.Jinan Univ, Inst Life & Hlth Engn, Guangzhou, Guangdong, Peoples R China;
5.Zhejiang Univ, Life Sci Inst, Hangzhou, Zhejiang, Peoples R China;
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou, Zhejiang, Peoples R China
通讯作者单位生命科学与技术学院
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GB/T 7714
Qin, Zhen,Sun, Honghua,Yue, Meiting,et al. Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis[J]. CELL DISCOVERY,2021,7(1).
APA Qin, Zhen.,Sun, Honghua.,Yue, Meiting.,Pan, Xinwen.,Chen, Liang.,...&Ji, Hongbin.(2021).Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis.CELL DISCOVERY,7(1).
MLA Qin, Zhen,et al."Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis".CELL DISCOVERY 7.1(2021).
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