Open AccessNanog maintains stemness of Lkb1 ‐deficient lung adenocarcinoma and prevents gastric differentiation
Author(s) -
Tong Xinyuan,
Chen Yueqing,
Zhu Xinsheng,
Ye Yi,
Xue Yun,
Wang Rui,
Gao Yijun,
Zhang Wenjing,
Gao Weiqiang,
Xiao Lei,
Chen Haiquan,
Zhang Peng,
Ji Hongbin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012627
Subject(s) - china , beijing , excellence , library science , sox2 , center of excellence , chinese academy of sciences , homeobox protein nanog , stem cell biology , medicine , biology , political science , embryonic stem cell , genetics , computer science , induced pluripotent stem cell , law , gene , embryo , reproductive technology , embryogenesis
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 γ‐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.