EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation PMID: 38284990

ADC Targets in Oncology

2026-04-10

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.

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.