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Published on: January 26, 2024
JAK2 Loss Arising From Tumor-Spread-Through-Air-Spaces (STAS) Promotes Tumor Progression by Suppressing CD8+ T Cells
Soohwan Choi1, Hyung Suk Kim2, Kyueng-Whan Min3
1Department of Thoracic and Cardiovascular Surgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea.
Background:
Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates.
Methods:
This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis.
Results:
The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression.
Conclusion:
In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.
Insights
Low Janus kinase 2 (JAK2) expression is linked to tumor spread through air spaces (STAS) in lung adenocarcinoma (LUAD), indicating poor prognosis and potential therapeutic targets. This finding may guide future LUAD treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Tumor spread through air spaces (STAS) is an emerging risk factor in lung adenocarcinoma (LUAD).
- Understanding genetic alterations and immune responses associated with STAS is crucial for improving patient outcomes.
- Janus kinase 2 (JAK2) is investigated for its role in LUAD prognosis and its relationship with STAS.
Purpose of the Study:
- To investigate the association between STAS and specific genetic alterations, focusing on JAK2.
- To analyze the impact of JAK2 expression on patient survival and anticancer immune responses in LUAD.
- To identify potential drug candidates targeting LUAD with low JAK2 expression.
Main Methods:
- Analysis of clinicopathological and genetic data from 566 LUAD patients.
- Application of gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, and gradient boosting machine (GBM) analysis.
- In vitro drug screening in lung cancer cell lines.
Main Results:
- Patients with STAS exhibited significantly shorter survival times (P < 0.001).
- STAS was associated with JAK2 downregulation, and low JAK2 expression correlated with poor prognosis and reduced CD8+ T-cell fractions.
- JAK2 improved survival prediction in GBM models, and several compounds (mirin, CCT007093, dihydroretenone, ABT737) inhibited cancer cell growth with low JAK2.
Conclusions:
- Low JAK2 expression in LUAD with STAS is an unfavorable prognostic factor.
- The link between JAK2 and CD8+ T cells suggests STAS impacts the anticancer immune response.
- Findings support further research into JAK2-targeted therapies for LUAD patients with STAS.
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