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Author Spotlight: Establishing a Murine Non-Small Cell Lung Cancer Model for Developing Nanoformulations of Anticancer Drugs
Published on: May 10, 2024
RGS2 promotes brain metastasis of cisplatin-resistant non-small cell lung cancer through caspase-1/IL-1beta signaling
Jiayi Lin1, Lun Liang2,3, Xupeng Zhu1
1Research Center for Protein and Cell-based Drugs, Guangdong-Hong Kong Joint Laboratory for Metabolic Medicine, Institutes of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Background:
Brain metastases are a leading cause of mortality in non-small cell lung cancer (NSCLC) patients. Chemoresistance-induced metastasis remains a significant challenge in NSCLC. This study investigates whether cisplatin resistance enhances brain metastasis in NSCLC and examines the associated molecular mechanisms.
Methods:
Cisplatin-resistant NSCLC cell lines were established. Their brain metastatic capacity was assessed using an endothelial adhesion and blood-brain barrier (BBB) transmigration assay, as well as brain metastasis models. RNA-seq was performed to identify differentially expressed genes. The roles of key candidate molecules and mechanisms were validated through genetic and pharmacological inhibition approaches.
Results:
Cisplatin-resistant NSCLC cells exhibited markedly enhanced brain metastatic capacity compared to their parental counterparts, with increased adhesion to brain endothelial cells and transmigration across the BBB in vitro, and more and larger brain metastatic lesions in vivo. RGS2 was revealed to be significantly upregulated in cisplatin-resistant and brain metastatic NSCLC cells, and was associated with an unfavorable prognosis in lung adenocarcinoma patients. RGS2 knockdown diminished the brain metastatic capacity of cisplatin-resistant NSCLC cells. Mechanistically, RGS2 activated the caspase-1/IL-1beta signaling pathway, promoting tumor cell-endothelial adhesion through VCAM-1 upregulation and compromising BBB integrity through Claudin-5 downregulation. Knockdown or pharmacological inhibition of caspase-1 counteracted these effects and mitigated RGS2-driven brain metastasis in vivo.
Conclusions:
Cisplatin resistance promotes brain metastasis in NSCLC through the RGS2/caspase-1/IL-1beta signaling. Targeting this pathway may offer a promising preventive strategy to reduce and curb brain metastasis in chemotherapy-resistant NSCLC. Moreover, RGS2 shows potential as a biomarker for monitoring and predicting NSCLC brain metastasis.
Insights
Cisplatin resistance in non-small cell lung cancer (NSCLC) enhances brain metastasis. This is driven by RGS2 activation of caspase-1/IL-1beta signaling, suggesting a new therapeutic target for NSCLC brain metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Brain metastases are a primary cause of death in non-small cell lung cancer (NSCLC).
- Chemoresistance-induced metastasis presents a major clinical challenge in NSCLC management.
- Understanding the mechanisms linking chemoresistance to brain metastasis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate if cisplatin resistance enhances brain metastasis in NSCLC.
- To elucidate the molecular mechanisms underlying cisplatin resistance-driven brain metastasis.
- To identify potential therapeutic targets and biomarkers for NSCLC brain metastasis.
Main Methods:
- Established cisplatin-resistant NSCLC cell lines for experimental models.
- Assessed brain metastatic capacity using in vitro adhesion and transmigration assays, and in vivo metastasis models.
- Utilized RNA sequencing to identify differentially expressed genes and validated key molecular players through genetic and pharmacological inhibition.
Main Results:
- Cisplatin-resistant NSCLC cells demonstrated significantly increased brain metastatic potential.
- RGS2 was found to be upregulated in resistant cells and associated with poor prognosis, and its knockdown reduced metastatic capacity.
- RGS2 was shown to activate caspase-1/IL-1beta signaling, promoting endothelial adhesion and compromising blood-brain barrier integrity.
Conclusions:
- Cisplatin resistance promotes NSCLC brain metastasis via the RGS2/caspase-1/IL-1beta pathway.
- Targeting this pathway offers a potential strategy to prevent brain metastasis in chemotherapy-resistant NSCLC.
- RGS2 may serve as a valuable biomarker for predicting and monitoring NSCLC brain metastasis.
