2. Academic Validation
  3. TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition

TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition

  • J Exp Med. 2024 Jul 1;221(7):e20240111. doi: 10.1084/jem.20240111.
Yun Xue # 1 2 3,  Yuting Chen # 2 4,  Sijia Sun # 5,  Xinyuan Tong # 2,  Yujia Chen 5,  Shijie Tang 2,  Xue Wang 2,  Simin Bi 6,  Yuqin Qiu 7,  Qiqi Zhao 1 2 4,  Zhen Qin 2,  Qin Xu 2,  Yingjie Ai 8,  Leilei Chen 5,  Beizhen Zhang 3,  Zhijie Liu 6,  Minbiao Ji 6,  Meidong Lang 7 9,  Luonan Chen 2 4 10,  Guoliang Xu 11 12,  Liang Hu 2,  Dan Ye 5,  Hongbin Ji 1 2 4
Affiliations

Affiliations

  • 1 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , Hangzhou, China.
  • 2 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences , Shanghai, China.
  • 3 University of Chinese Academy of Sciences , Beijing, China.
  • 4 School of Life Science and Technology, Shanghai Tech University , Shanghai, China.
  • 5 Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University , Shanghai, China.
  • 6 Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China.
  • 7 Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology , Shanghai, China.
  • 8 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 9 Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 10 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming, China.
  • 11 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai, China.
  • 12 Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069) , Shanghai, China.
  • # Contributed equally.
PMID: 38805014 DOI: 10.1084/jem.20240111
Abstract

Phenotypic plasticity is a rising Cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung Cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that TET2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.

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