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

Zhen Qin; Meiting Yue; Shijie Tang; Fengying Wu; Honghua Sun; Yuan Li; Yongchang Zhang; Hiroki Izumi; Hsinyi Huang; Wanying Wang; Yun Xue; Xinyuan Tong; Shunta Mori; Tetsuro Taki; Koichi Goto; Yujuan Jin; Fei Li; Fu-Ming Li; Yijun Gao; Zhaoyuan Fang; Yisheng Fang; Liang Hu; Xiumin Yan; Guoliang Xu; Haiquan Chen; Susumu S Kobayashi; Andrea Ventura; Kwok-Kin Wong; Xueliang Zhu; Liang Chen; Shengxiang Ren; Luo-Nan Chen; Hongbin Ji

doi:10.1084/jem.20232028

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. Epub 2024 Jan 29.

Authors

Zhen Qin^#¹, Meiting Yue^#^{1

2}, Shijie Tang^#¹, Fengying Wu^#³, Honghua Sun^#^{1

2}, Yuan Li^{4

5}, Yongchang Zhang⁶, Hiroki Izumi⁷, Hsinyi Huang⁸, Wanying Wang³, Yun Xue^{1

9}, Xinyuan Tong¹, Shunta Mori⁷, Tetsuro Taki⁷, Koichi Goto⁷, Yujuan Jin¹, Fei Li⁵, Fu-Ming Li¹⁰, Yijun Gao¹¹, Zhaoyuan Fang¹², Yisheng Fang¹³, Liang Hu¹, Xiumin Yan¹⁴, Guoliang Xu^{15

16}, Haiquan Chen^{4

5}, Susumu S Kobayashi¹⁷, Andrea Ventura¹⁸, Kwok-Kin Wong⁸, Xueliang Zhu^{1

2

16}, Liang Chen¹⁹, Shengxiang Ren³, 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.

MeSH terms

Adenocarcinoma of Lung*
Animals
Carcinoma, Squamous Cell*
Humans
Lung
Lung Neoplasms* / genetics
Mice
Oncogene Proteins, Fusion / genetics
Receptor Protein-Tyrosine Kinases

Substances

Receptor Protein-Tyrosine Kinases
EML4-ALK fusion protein, human
Oncogene Proteins, Fusion

Abstract

MeSH terms

Substances

Grants and funding