2. Academic Validation
  3. EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation

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

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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