EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation-Reference-Cited by-同舟云学术

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

Published:2024-01-29 Issue:3 Volume:221 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Qin Zhen¹^ORCID,Yue Meiting¹²^ORCID,Tang Shijie¹^ORCID,Wu Fengying³^ORCID,Sun Honghua¹²^ORCID,Li Yuan⁴⁵^ORCID,Zhang Yongchang⁶^ORCID,Izumi Hiroki⁷^ORCID,Huang Hsinyi⁸^ORCID,Wang Wanying³^ORCID,Xue Yun¹⁹^ORCID,Tong Xinyuan¹^ORCID,Mori Shunta⁷^ORCID,Taki Tetsuro⁷^ORCID,Goto Koichi⁷^ORCID,Jin Yujuan¹^ORCID,Li Fei⁵^ORCID,Li Fu-Ming¹⁰^ORCID,Gao Yijun¹¹^ORCID,Fang Zhaoyuan¹²^ORCID,Fang Yisheng¹³^ORCID,Hu Liang¹^ORCID,Yan Xiumin¹⁴^ORCID,Xu Guoliang¹⁵¹⁶^ORCID,Chen Haiquan⁴⁵^ORCID,Kobayashi Susumu S.¹⁷^ORCID,Ventura Andrea¹⁸^ORCID,Wong Kwok-Kin⁸^ORCID,Zhu Xueliang¹²¹⁶^ORCID,Chen Liang¹⁹^ORCID,Ren Shengxiang³^ORCID,Chen Luo-Nan¹²¹⁶⁹^ORCID,Ji Hongbin¹²¹⁶⁹^ORCID

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 1 , Shanghai, China

2. University of Chinese Academy of Sciences 2 , Beijing, China

3. Shanghai Pulmonary Hospital, Tongji University School of Medicine 3 Department of Medical Oncology, , Shanghai, China

4. Fudan University Shanghai Cancer Center 5 Department of Thoracic Surgery, , Shanghai, China

5. Shanghai Medical College, Fudan University 9 Department of Oncology, , Shanghai, China

6. Hunan Cancer Hospital, Central South University 6 Department of Medical Oncology, , Changsha, China

7. National Cancer Center Hospital East 7 Department of Thoracic Oncology, , Kashiwa, Japan

8. Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York University Langone Health 8 , New York, NY, USA

9. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences 19 , Hangzhou, China

10. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University 10 , Shanghai, China

11. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center 11 , Guangzhou, China

12. University of Edinburgh Institute, Zhejiang University 12 , Haining, China

13. Nanfang Hospital, Southern Medical University 13 Department of Oncology, , 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 14 , 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 15 , Shanghai, China

16. School of Life Science and Technology, Shanghai Tech University 18 , Shanghai, China

17. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center 16 Division of Translational Genomics, , Kashiwa, Japan

18. Memorial Sloan Kettering Cancer Center 17 Cancer Biology and Genetics Program, , 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 4 , Guangzhou, China

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.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Chinese Academy of Science

Innovative Research Team of High-level Local Universities in Shanghai

Publisher

Rockefeller University Press

Link

https://rupress.org/jem/article-pdf/doi/10.1084/jem.20232028/1923498/jem_20232028.pdf

Reference96 articles.

1. Acquired resistance to KRASG12C inhibition in cancer;Awad;N. Engl. J. Med.,2021