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

Author:

Tang Shijie1,Xue Yun123,Qin Zhen1,Fang Zhaoyuan145,Sun Yihua67,Yuan Chongzhe67,Pan Yunjian67,Zhao Yue67,Tong Xinyuan1,Zhang Jian1,Huang Hsinyi1,Chen Yuting18,Hu Liang1ORCID,Huang Dasong9,Wang Ruiqi9,Zou Weiguo1,Li Yuan67,Thomas Roman K101112,Ventura Andrea13,Wong Kwok-Kin14ORCID,Chen Haiquan67ORCID,Chen Luonan1815ORCID,Ji Hongbin1816ORCID

Affiliation:

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   , Beijing 100049 , China

3. of Chinese Academy of Sciences   , Beijing 100049 , China

4. Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine , Haining 314400 , China

5. The Second Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou 310000 , China

6. Department of Thoracic Surgery, Fudan University Shanghai Cancer Center , Shanghai 200032 , China

7. Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China

8. School of Life Science and Technology, Shanghai Tech University , Shanghai 200120 , China

9. Department of Mathematics, Shanghai University , Shanghai 200444 , China

10. Department

11. of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne 50931, Germany

12. Department of Pathology, University Hospital Cologne , Cologne 50937 , Germany

13. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center , New York, NY 10065 , USA

14. Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center , New York , NY 10016 , USA

15. Key Laboratory of Systems Biology , Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

16. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences , Hangzhou 310024 , China

Abstract

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.

Funder

National Basic Research Program of China

Chinese Academy of Sciences

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Youth Innovation Promotion Association, Chinese Academy of Sciences

Special Fund for Science and Technology Innovation Strategy of Guangdong Province

Major Key Project of Peng Cheng Laboratory

JST Moonshot R&D

Publisher

Oxford University Press (OUP)

Subject

Multidisciplinary

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