期刊
CLINICAL AND TRANSLATIONAL MEDICINE
卷 12, 期 6, 页码 -出版社
JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.885
关键词
Cerebrospinal fluid; circulating tumour cells; gene regulatory networks; leptomeningeal metastases; tumour microenvironment
资金
- National Natural Science Foundation of China [82072367, 82102489, 81672100]
- Key Laboratory for Laboratory Medicine of Jiangsu Province of China [ZDXKB2016005]
- National Key Research and Development Program of China [2017YFA0103902]
- Innovative Research Team of High-level Local Universities in Shanghai [SSMU-ZDCX20180700]
- Key Laboratory Program of the Education Commission of Shanghai Municipality [ZDSYS14005]
This study examined the cerebrospinal fluid (CSF) tumor microenvironment (TME) of patients with leptomeningeal metastases (LM) using single-cell RNA sequencing (scRNA-seq). The analysis revealed the presence of M2-subtype macrophages and regulatory T cells, indicating an immunosuppressive tumor immunity direction in LM patients. Furthermore, the CSF circulating tumor cells (CTCs) of breast cancer LM patients were classified into five molecular subtypes and showed heterogeneity in cell proliferation and cancer-testis antigen expression. The study provides insights into the mechanism research, diagnosis, and therapy of LM.
Leptomeningeal metastases (LM) occur in patients with breast cancer (BC) and lung cancer (LC) showing exceptionally poor prognosis. The cerebrospinal fluid (CSF) tumour microenvironment (TME) of LM patients is not well defined at a single-cell level. Based on the 10x genomics single-cell RNA sequencing (scRNA-seq) data from GEO database including five patient-derived CSF samples of BC-LM and LC-LM, and four patient-derived CSF samples of idiopathic intracranial hypertension (IIH) as controls, we analysed single-cell transcriptome characteristics of CSF TME in LM patients compared to controls simultaneously and comprehensively. In addition, we performed 10x genomics scRNA-seq on CSF cells derived from a BC-LM patient to help generate a solid conclusion. The CSF macrophages in LM patients showing M2-subtype signature and the emergence of regulatory T cells in LM confirmed the direction of tumour immunity toward immunosuppression. Then, the characteristics of CSF circulating tumour cells (CTCs) of breast cancer LM (BC-LM) patients were classified into five molecular subtypes by PAM50 model. The communication between macrophages and five subtype-specific CSF-CTCs showed largest number of ligand-receptor interactions. The five subtypes-specific CSF-CTCs showed great heterogeneities which were manifested in cell proliferation and cancer-testis antigens expression. Gene regulatory networks (GRNs) analysis revealed that transcription factor SREBF2 was universally activated in the five subtypes-specific CSF-CTCs. Our results will provide inspiration on new directions of the mechanism research, diagnosis and therapy of LM.
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