EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation Journal Article
| Authors: | Qin, Z.; Yue, M.; Tang, S.; Wu, F.; Sun, H.; Li, Y.; Zhang, Y.; Izumi, H.; Huang, H.; Wang, W.; Xue, Y.; Tong, X.; Mori, S.; Taki, T.; Goto, K.; Jin, Y.; Li, F.; Li, F. M.; Gao, Y.; Fang, Z.; Fang, Y.; Hu, L.; Yan, X.; Xu, G.; Chen, H.; Kobayashi, S. S.; Ventura, A.; Wong, K. K.; Zhu, X.; Chen, L.; Ren, S.; Chen, L. N.; Ji, H. |
| Article Title: | EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation |
| 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. © 2024 Qin et al. |
| Keywords: | immunohistochemistry; controlled study; unclassified drug; human cell; nonhuman; mouse; phenotype; animal tissue; animal experiment; animal model; immunofluorescence; lung adenocarcinoma; janus kinase; cell subpopulation; upregulation; stat protein; peptides and proteins; phase separation; ruxolitinib; human; male; article; squamous cell lung carcinoma; organoid; lorlatinib; jak-stat signaling; single cell rna seq; protein alk; protein eml4 |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 221 |
| Issue: | 3 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2024-03-04 |
| Start Page: | e20232028 |
| Language: | English |
| DOI: | 10.1084/jem.20232028 |
| PROVIDER: | scopus |
| PMCID: | PMC10824105 |
| PUBMED: | 38284990 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
