EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation

  • J Exp Med. 2024 Mar 4;221(3):e20232028. doi: 10.1084/jem.20232028.
Zhen Qin  #  1 ,  Meiting Yue  #  1  2 ,  Shijie Tang  #  1 ,  Fengying Wu  #  3 ,  Honghua Sun  #  1  2 ,  Yuan Li  4  5 ,  Yongchang Zhang  6 ,  Hiroki Izumi  7 ,  Hsinyi Huang  8 ,  Wanying Wang  3 ,  Yun Xue  1  9 ,  Xinyuan Tong  1 ,  Shunta Mori  7 ,  Tetsuro Taki  7 ,  Koichi Goto  7 ,  Yujuan Jin  1 ,  Fei Li  5 ,  Fu-Ming Li  10 ,  Yijun Gao  11 ,  Zhaoyuan Fang  12 ,  Yisheng Fang  13 ,  Liang Hu  1 ,  Xiumin Yan  14 ,  Guoliang Xu  15  16 ,  Haiquan Chen  4  5 ,  Susumu S Kobayashi  17 ,  Andrea Ventura  18 ,  Kwok-Kin Wong  8 ,  Xueliang Zhu  1  2  16 ,  Liang Chen  19 ,  Shengxiang Ren  3 ,  Luo-Nan Chen  1  2  16  9 ,  Hongbin Ji  1  2  16  9
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 Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4. Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 6. Department of Medical Oncology, Hunan Cancer Hospital, Central South University, Changsha, China.
  • 7. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 8. Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York University Langone Health , New York, NY, USA.
  • 9. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , Hangzhou, China.
  • 10. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University , Shanghai, China.
  • 11. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
  • 12. University of Edinburgh Institute, Zhejiang University , Haining, China.
  • 13. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 14. Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China.
  • 15. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences , Shanghai, China.
  • 16. School of Life Science and Technology, Shanghai Tech University , Shanghai, China.
  • 17. Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
  • 18. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 19. Ministry of Education Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University , Guangzhou, China.
  • # Contributed equally.
PMID: 38284990 DOI: 10.1084/jem.20232028
Abstract

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong Cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives Lung Adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in Organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous Tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged Tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

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