USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity
Abstract Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. Here, we established a novel mouse model of LUSC by overexpressing USP13 on KrasG12D/+; Trp...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-12-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-023-01892-x |
| _version_ | 1797388472272551936 |
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| author | Juntae Kwon Jinmin Zhang Boram Mok Samuel Allsup Chul Kim Jeffrey Toretsky Cecil Han |
| author_facet | Juntae Kwon Jinmin Zhang Boram Mok Samuel Allsup Chul Kim Jeffrey Toretsky Cecil Han |
| author_sort | Juntae Kwon |
| collection | DOAJ |
| description | Abstract Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. Here, we established a novel mouse model of LUSC by overexpressing USP13 on KrasG12D/+; Trp53flox/flox background (KPU). KPU-driven lung squamous tumors faithfully recapitulate key pathohistological, molecular features, and cellular pathways of human LUSC. We found that USP13 altered lineage-determining factors such as NKX2-1 and SOX2 in club cells of the airway and reinforced the fate of club cells to squamous carcinoma development. We showed a strong molecular association between USP13 and c-MYC, leading to the upregulation of squamous programs in murine and human lung cancer cells. Collectively, our data demonstrate that USP13 is a molecular driver of lineage plasticity in club cells and provide mechanistic insight that may have potential implications for the treatment of LUSC. Graphical Abstract |
| first_indexed | 2024-03-08T22:41:19Z |
| format | Article |
| id | doaj.art-626e7d518b9846f0ac8bdcb42a97e591 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-08T22:41:19Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-626e7d518b9846f0ac8bdcb42a97e5912023-12-17T12:08:58ZengBMCMolecular Cancer1476-45982023-12-0122112410.1186/s12943-023-01892-xUSP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticityJuntae Kwon0Jinmin Zhang1Boram Mok2Samuel Allsup3Chul Kim4Jeffrey Toretsky5Cecil Han6Department of Oncology, Georgetown University School of MedicineDepartment of Biochemistry and Molecular & Cellular Biology, Georgetown University School of MedicineDepartment of Oncology, Georgetown University School of MedicineDepartment of Biochemistry and Molecular & Cellular Biology, Georgetown University School of MedicineDivision of Hematology and Oncology, Georgetown University School of MedicineDepartment of Oncology, Georgetown University School of MedicineDepartment of Oncology, Georgetown University School of MedicineAbstract Lung squamous cell carcinoma (LUSC) is associated with high mortality and limited targeted therapies. USP13 is one of the most amplified genes in LUSC, yet its role in lung cancer is largely unknown. Here, we established a novel mouse model of LUSC by overexpressing USP13 on KrasG12D/+; Trp53flox/flox background (KPU). KPU-driven lung squamous tumors faithfully recapitulate key pathohistological, molecular features, and cellular pathways of human LUSC. We found that USP13 altered lineage-determining factors such as NKX2-1 and SOX2 in club cells of the airway and reinforced the fate of club cells to squamous carcinoma development. We showed a strong molecular association between USP13 and c-MYC, leading to the upregulation of squamous programs in murine and human lung cancer cells. Collectively, our data demonstrate that USP13 is a molecular driver of lineage plasticity in club cells and provide mechanistic insight that may have potential implications for the treatment of LUSC. Graphical Abstracthttps://doi.org/10.1186/s12943-023-01892-xUSP13c-MycLung squamous cell carcinomaLineage plasticityGEMM |
| spellingShingle | Juntae Kwon Jinmin Zhang Boram Mok Samuel Allsup Chul Kim Jeffrey Toretsky Cecil Han USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity Molecular Cancer USP13 c-Myc Lung squamous cell carcinoma Lineage plasticity GEMM |
| title | USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity |
| title_full | USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity |
| title_fullStr | USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity |
| title_full_unstemmed | USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity |
| title_short | USP13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity |
| title_sort | usp13 drives lung squamous cell carcinoma by switching lung club cell lineage plasticity |
| topic | USP13 c-Myc Lung squamous cell carcinoma Lineage plasticity GEMM |
| url | https://doi.org/10.1186/s12943-023-01892-x |
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