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  3. Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment

Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment

  • Natl Sci Rev. 2023 Feb 14;10(4):nwad028. doi: 10.1093/nsr/nwad028.
Shijie Tang 1,  Yun Xue 1 2,  Zhen Qin 1,  Zhaoyuan Fang 1 3 4,  Yihua Sun 5 6,  Chongzhe Yuan 5 6,  Yunjian Pan 5 6,  Yue Zhao 5 6,  Xinyuan Tong 1,  Jian Zhang 1,  Hsinyi Huang 1,  Yuting Chen 1 7,  Liang Hu 1,  Dasong Huang 8,  Ruiqi Wang 8,  Weiguo Zou 1,  Yuan Li 5 6,  Roman K Thomas 9 10,  Andrea Ventura 11,  Kwok-Kin Wong 12,  Haiquan Chen 5 6,  Luonan Chen 1 7 13,  Hongbin Ji 1 7 14
Affiliations

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 200031, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining 314400, China.
  • 4 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
  • 5 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
  • 6 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 7 School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China.
  • 8 Department of Mathematics, Shanghai University, Shanghai 200444, China.
  • 9 Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne 50931, Germany.
  • 10 Department of Pathology, University Hospital Cologne, Cologne 50937, Germany.
  • 11 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 12 Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
  • 13 Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 14 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 37051524 DOI: 10.1093/nsr/nwad028
Abstract

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, harbors strong plasticity and is significantly associated with poor prognosis. We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation. Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development. Dynamic dysregulation of the counteracting lineage-specific transcription factors (TFs), containing adenomatous TFs NKX2-1 and FOXA2, and squamous TFs TP63 and SOX2, finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration. Genomic clustering identified the most malignant subtype featured with STK11-inactivation, and targeting LSD1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors. These data collectively uncover the comprehensive molecular landscape, oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS.

Keywords

ALK fusion; CXCL3/CXCL5; LSD1; LUAS; counteracting TF regulatory network.

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