Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation

doi:10.15252/emmm.202012627

	Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation
	Tong, Xinyuan 1; Chen, Yueqing 1,2; Zhu, Xinsheng 3; Ye, Yi4 ; Xue, Yun 1,2; Wang, Rui 5,6; Gao, Yijun 1; Zhang, Wenjing 1; Gao, Weiqiang 7,8; Xiao, Lei 9,10; Chen, Haiquan 5,6; Zhang, Peng 3; Ji, Hongbin1,2,3,4
	2021-01-13
发表期刊	EMBO MOLECULAR MEDICINE (IF:9.0[JCR-2023],11.0[5-Year])
ISSN	1757-4676
发表状态	已发表
DOI	10.15252/emmm.202012627
摘要	Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the Kras(LSL-G12D/+); Lkb1(flox/flox) (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the gamma-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.
关键词	drug resistance gastric differentiation LKB1 Nanog Notch
收录类别	SCI ; SCIE
语种	英语
资助项目	National Basic Research Program of China[2017YFA0505501] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB19020201] ; National Natural Science Foundation of China[31621003][81872312][91731314][81430066][81871875][81802279][81902326] ; Basic Frontier Scientific Research Program of Chinese Academy of Science[ZDBS-LY-SM006] ; State Key Laboratory of Oncogenes and Related Genes[KF-20-03] ; China Postdoctoral Science Foundation[2016M601667]
WOS研究方向	Research & Experimental Medicine
WOS类目	Medicine, Research & Experimental
WOS记录号	WOS:000607240600001
出版者	WILEY
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/125047
专题	生命科学与技术学院_硕士生生命科学与技术学院_特聘教授组_季红斌组
通讯作者	Zhang, Peng; 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.Tongji Univ, Sch Med, Shanghai Pulm Hosp, Dept Thorac Surg, Shanghai, Peoples R China 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 5.Fudan Univ, Shanghai Canc Ctr, Dept Thorac Surg, Shanghai, Peoples R China 6.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China 7.Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Renji Hosp, Shanghai Canc Inst,Sch Med, Shanghai, Peoples R China 8.Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai, Peoples R China 9.Zhejiang Univ, Coll Anim Sci, Hangzhou, Peoples R China 10.Zhejiang Univ, Sch Med, Hangzhou, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Tong, Xinyuan,Chen, Yueqing,Zhu, Xinsheng,et al. Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation[J]. EMBO MOLECULAR MEDICINE,2021.
APA	Tong, Xinyuan.,Chen, Yueqing.,Zhu, Xinsheng.,Ye, Yi.,Xue, Yun.,...&Ji, Hongbin.(2021).Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.EMBO MOLECULAR MEDICINE.
MLA	Tong, Xinyuan,et al."Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation".EMBO MOLECULAR MEDICINE (2021).