Single-cell transcriptomic analysis of the senescent microenvironment in bone metastasis.

Area of Science:

• Oncology
• Cancer Biology
• Molecular Biology

Background:

• Bone metastasis (BM) is a critical factor in cancer mortality, particularly from non-small cell lung cancer (NSCLC).
• The molecular mechanisms governing the bone metastatic microenvironment remain incompletely understood, limiting therapeutic advancements.

Purpose of the Study:

• To investigate the cellular and molecular characteristics of the bone metastatic niche in NSCLC.
• To identify key cellular players and pathways involved in NSCLC bone metastasis.

Main Methods:

• Single-cell transcriptomic analysis of primary tumors and bone metastasis tissues/blood.
• Validation using multiplex immunofluorescence staining and public datasets.

Main Results:

• NSCLC bone metastasis exhibits a senescent microenvironment with increased senescent malignant cells and aggravated metastatic properties.
• Endothelial-mesenchymal transition via SOX18 activation contributes to vascular endothelial cell senescence in BM.
• CD4+ T cells in a stressed, senescent state are enriched in BM, impairing immune surveillance.
• The SPP1 pathway mediates crosstalk between T cells, endothelial cells, and malignant cells, activating SOX18 and worsening survival.

Conclusions:

• Cellular senescence plays a pivotal role in shaping the NSCLC bone metastatic microenvironment.
• Targeting cellular senescence presents a potential therapeutic strategy for advanced NSCLC patients with bone metastasis.