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

Xinyuan Tong; Yueqing Chen; Xinsheng Zhu; Yi Ye; Yun Xue; Rui Wang; Yijun Gao; Wenjing Zhang; Weiqiang Gao; Lei Xiao; Haiquan Chen; Peng Zhang; Hongbin Ji

doi:10.15252/emmm.202012627

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

EMBO Mol Med. 2021 Mar 5;13(3):e12627. doi: 10.15252/emmm.202012627. Epub 2021 Jan 13.

Authors

Xinyuan Tong¹, Yueqing Chen^{1

2}, Xinsheng Zhu³, Yi Ye⁴, Yun Xue^{1

2}, Rui Wang^{5

6}, Yijun Gao¹, Wenjing Zhang¹, Weiqiang Gao^{7

8}, Lei Xiao⁹, Haiquan Chen^{5

6}, Peng Zhang³, Hongbin Ji^{1

2

3

4}

Affiliations

¹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
⁵ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁷ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
⁹ College of Animal Science and Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.

Abstract

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.

Keywords: Nanog; LKB1; Notch; drug resistance; gastric differentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
Adenocarcinoma of Lung* / genetics
Animals
Cell Differentiation
Disease Models, Animal
Humans
Lung Neoplasms*
Mice
Nanog Homeobox Protein / genetics
Neoplastic Stem Cells
Protein Serine-Threonine Kinases
Signal Transduction

Substances

NANOG protein, human
Nanog Homeobox Protein
Protein Serine-Threonine Kinases
STK11 protein, human
AMP-Activated Protein Kinase Kinases