| Accession |
PRJCA013746 |
| Title |
EML4-ALK fusions drive lung adeno-to-squamous transdifferentiation through phase separation-mediated JAK-STAT activation |
| Relevance |
Medical |
| Data types |
Transcriptome or Gene expression
Single cell sequencing
|
| Organisms |
Homo sapiens
|
| Description |
Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibit strong cancer plasticity. We find that ALK-rearrangement is detectable in 5.1-7.5% human LUAS and transgenic expression of EML4-ALK fusion drives lung adenocarcinoma (LUAD) formation initially and squamous transformation at late stage. We identify club cells as the main cell-of-origin for squamous transformation. Through recapitulating such lineage transition in organoids system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transformation. 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. |
| Sample scope |
Multispecies |
| Release date |
2022-12-08 |
| Publication |
| PubMed ID |
Article title |
Journal name |
DOI |
Year |
| 38284990
|
EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation
|
Journal of Experimental Medicine
|
10.1084/jem.20232028
|
2024
|
|
|
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| No funding support
|
|
|
|
|
|
| Submitter |
Shijie
Tang (tangshijie6@sibcb.ac.cn)
|
| Organization |
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences |
| Submission date |
2022-12-08 |
