Single-cell transcriptomic analysis of the senescent microenvironment in bone metastasis.
Shenglin WangLu AoHuangfeng LinHongxiang WeiZhaoyang WuShuting LuFude LiangRongkai ShenHuarong ZhangTongjie MiaoXiaopei ShenJianhua LinGuangxian ZhongPublished in: Cell proliferation (2024)
Bone metastasis (BM) is a mortality-related event of late-stage cancer, with non-small cell lung cancer (NSCLC) being a common origin for BM. However, the detailed molecular profiling of the metastatic bone ecosystem is not fully understood, hindering the development of effective therapies for advanced patients. In this study, we examined the cellular heterogeneity between primary tumours and BM from tissues and peripheral blood by single-cell transcriptomic analysis, which was verified using multiplex immunofluorescence staining and public datasets. Our results demonstrate a senescent microenvironment in BM tissues of NSCLC. BM has a significantly higher infiltration of malignant cells with senescent characteristics relative to primary tumours, accompanied by aggravated metastatic properties. The endothelial-mesenchymal transition involved with SOX18 activation is related to the cellular senescence of vascular endothelial cells from BM. CD4Tstr cells, with pronounced stress and senescence states, are preferentially infiltrated in BM, indicating stress-related dysfunction contributing to the immunocompromised environment during tumour metastasis to bone. Moreover, we identify the SPP1 pathway-induced cellular crosstalk among T cells, vascular ECs and malignant cells in BM, which activates SOX18 and deteriorates patient survival. Our findings highlight the roles of cellular senescence in modulating the microenvironment of BM and implicate anti-senescence therapy for advanced NSCLC patients.
Keyphrases
- single cell
- small cell lung cancer
- stem cells
- induced apoptosis
- endothelial cells
- end stage renal disease
- rna seq
- cell cycle arrest
- bone mineral density
- dna damage
- newly diagnosed
- stress induced
- ejection fraction
- peripheral blood
- high throughput
- peritoneal dialysis
- healthcare
- soft tissue
- signaling pathway
- risk assessment
- endoplasmic reticulum stress
- type diabetes
- advanced non small cell lung cancer
- climate change
- cardiovascular disease
- bone loss
- young adults
- risk factors
- intensive care unit
- tyrosine kinase
- postmenopausal women
- brain metastases
- body composition
- human health
- electronic health record
- patient reported
- lymph node metastasis
- patient reported outcomes
- adverse drug