The Therapeutic Potential of ADAMTS8 in Lung Adenocarcinoma without Targetable Therapy
Hsiao-Chen Lee1,2, Chao-Yuan Chang1,3, Kuan-Li Wu1,4
1Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Abstract:
Lung cancer is well known for its high mortality worldwide. The treatment for advanced lung cancer needs more attention to improve its survival time. A disintegrin and metallopeptidase with thrombospondin motifs 8 (ADAMTS8) has been linked to several cancer types. However, its role in lung cancer is worthy of deep investigation to promote novel drug development. This study took advantage of RNA-seq and bioinformatics to verify the role that ADAMTS8 plays in lung cancer. The functional assays suggested that ADAMTS8 mediates invasion and metastasis when expressed at a low level, contributing to poor overall survival (OS). The expression of ADAMTS8 was under the regulation of GATA Binding Protein 1 (GATA1) and executed its pathologic role through Thrombospondin Type 1 Domain Containing 1 (THSD1) and ADAMTS Like 2 (ADAMTSL2). To define the impact of ADAMTS8 in the lung cancer treatment strategy, this study further grouped lung cancer patients in the TCGA database into mutated epidermal growth factor receptor (EGFR)/wild-type EGFR and programmed death ligand 1 (PD-L1) high/low groups. Importantly, the expression of ADAMTS8 was correlated positively with the recruitment of anticancer NKT cells and negatively with the infiltration of immunosuppressive Treg and exhausted T cells. The results indicated that lung cancer patients with higher ADAMTS8 levels among wild-type EGFR or low PD-L1 groups survive longer than those with lower levels do. This study indicates that ADAMTS8 might be a treatment option for patients with lung adenocarcinoma who lack efficient targeted or immunotherapies.
Insights
Low expression of ADAMTS8 in lung cancer correlates with increased metastasis and poor survival. Higher ADAMTS8 levels may improve outcomes in specific patient groups, suggesting its potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Lung cancer exhibits high mortality, necessitating improved treatments for advanced stages.
- A disintegrin and metallopeptidase with thrombospondin motifs 8 (ADAMTS8) is implicated in various cancers, but its specific role in lung cancer requires elucidation for novel drug development.
Purpose of the Study:
- To investigate the role of ADAMTS8 in lung cancer progression, survival, and its potential as a therapeutic target.
- To explore the regulatory mechanisms and downstream pathways of ADAMTS8 in lung cancer.
- To assess the correlation of ADAMTS8 expression with patient subgroups and immune cell infiltration.
Main Methods:
- RNA-sequencing and bioinformatics analyses were employed to study ADAMTS8 expression.
- Functional assays were conducted to evaluate the impact of ADAMTS8 on cancer cell invasion and metastasis.
- TCGA database was utilized to analyze ADAMTS8 expression in relation to patient demographics, mutations (EGFR), PD-L1 status, and immune cell infiltration.
Main Results:
- Low ADAMTS8 expression was associated with increased lung cancer cell invasion and metastasis, correlating with poor overall survival.
- ADAMTS8 expression is regulated by GATA Binding Protein 1 (GATA1) and acts through Thrombospondin Type 1 Domain Containing 1 (THSD1) and ADAMTS Like 2 (ADAMTSL2).
- Higher ADAMTS8 levels correlated positively with anticancer NKT cell recruitment and negatively with immunosuppressive Treg and exhausted T cells. Patients with wild-type EGFR or low PD-L1 and higher ADAMTS8 showed improved survival.
Conclusions:
- ADAMTS8 plays a critical role in regulating lung cancer metastasis and patient survival.
- ADAMTS8 influences the tumor immune microenvironment by modulating immune cell infiltration.
- ADAMTS8 represents a potential therapeutic target for lung adenocarcinoma, particularly for patients lacking effective targeted or immunotherapies.
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