Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment PMID: 37051524

ADC Targets in Oncology

2026-04-10

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

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.

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.