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Gene expression profile at single cell level of cerebrospinal fluid (CSF) cells from lung adenocarcinoma leptomeningeal metastases patients (LUAD LM)

ABSTRACT: Lung adenocarcinoma (LUAD)-derived leptomeningeal metastases (LM) represent a predominant subtype among all LM cases. Nevertheless, the cerebrospinal fluid (CSF) profile of LUAD-LM patients remains poorly characterized and reliable CSF diagnostic biomarkers for LUAD-LM have yet to be established. Using single-cell RNA sequencing data of CSF cells from six LUAD-LM patients, we drew a systematic transcriptomic atlas of the CSF cellular landscape. Our analysis revealed that LUAD-LM reprograms CSF into an immunosuppressive state, marked by the emergence of pro-tumoral LGMN-SELENOPhigh macrophages and proliferating CSF circulating tumor cells (CSF-CTC). Cell-cell communication analysis showed that CSF-CTC reinforces immunosuppression by co-inhibitory checkpoint axis NECTIN2_TIGIT axis with the CD8+T/NK cells, and via CD47_SIRPA axis with antigen-presenting cells. Furthermore, we identified the single-cell transcriptomic difference between CSF-CTC and tumor cells of parenchymal brain metastases (PBM). Notably, Trophoblast cell surface antigen 2 (TROP2) levels in CSF were significantly elevated in LUAD-LM patients versus both normal controls (NC) and LUAD patients without LM (Non-LM). It showed strong diagnostic accuracy for distinguishing LUAD LM from Non-LM or NC, and PBM did not influence the CSF TROP2 level. Collectively, our findings advance the understanding of LUAD-LM pathogenesis and highlight the potential of CSF TROP2 as a diagnostic biomarker for LM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276139 | GEO | 2026/04/03

REPOSITORIES: GEO

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Project description:Purpose: Leptomeningeal metastasis (LM) is a dismal terminal stage disease of solid cancer without definitive treatment. Both the limitation of cerebrospinal fluid (CSF) sample volume and a paucity of floating cancer cells are difficulties to study the genomic profiling of LM. As the profiling of microRNAs reflect the strategy and behavior of cancer cells to survive, and CSF is carrying micro-molecules from central nervous system (CNS), we evaluated the extracellular microRNA profiles of CSF from different CNS tumor status including LM. Materials and Methods: We prospectively collected CSF from 65 patients of five groups of cancer control (CC), healthy control (HC), LM, brain metastasis (BM); and brain tumor (BT). Extracellular RNA was extracted from 2 mL of CSF after proper cell down, and preceded to small RNA microarray with Affymetrix miRNA 4.0 microarray chips. Results: The mean RNA yield of LM patients was significantly higher compared to that of other patients groups (9.28 vs. 6.30 ㎍, p = 0.003). The small RNA (< 70 nucleotides) percentage was the highest in controls than that of other groups (53% vs. 26%, p < 0.001). Among 6,599 small RNA probes, mature microRNAs showed higher expression than that of pre-microRNAs and small nucleolar RNAs. The number of probes with the Present call in all samples is 22 mature microRNAs, 18 pre-mature microRNAs, and 27 small nucleolar RNAs. Expression value of mature microRNAs regarding their direction of 5 prime (5p) and 3 prime (3p), the expression of 3p microRNA is higher than those of 5p microRNA in both LM and BM samples (p < 0.001). Both supervised and unsupervised hierarchical clustering of 263 microRNAs, which showed more than 2 fold change at a significance level of p < 0.05, can differentiate LM from other CNS tumor patient groups. Prediction analysis of microarray (PAM) identified 13 microRNAs differentiate LM group from others including hsa-miR-335-5p and hsa-miR-466. MicroRNA profiling using significance of analysis of microarrays (SAM) analysis did not differentiate HC and CC. Whereas CSF samples from patients with LM showed the most number of 108 differentially expressed (more than 2 fold change) microRNAs compared to control group and also revealed 36 differentially expressed microRNAs between LM and BM including hsa-miR-466, hsa-miR-190a-3p, hsa-miR-98-3p, hsa-miR-34b-3p and so on. Representative discriminative microRNAs from microarray data were confirmed their expression level by digital droplet PCR in available CSF samples among the microarray samples. Gene Set Enrichment Analysis was performed using both 10 highly expressed and 6 suppressed microRNAs between LM and BM after normalization and 13 microRNAs from PAM analysis. The most targeted pathway was ‘positive-/ negative-transcription from RNA polymerase II promoter followed by ‘positive regulation of transcription, DNA-templated’ by discriminative microRNAs. When pathways were denoted by microRNAs from PAM, the most enriched pathway was inflammatory response and transcription relative to immune response. Conclusion: We performed extracellular small RNA microarray successfully with small volume of CSF. Analysis of profiles of microRNA according to patients with various CNS tumor status suggested the unique profiles might responsible for leptomeningeal metastasis.

Project description:Despite declining incidence and improved survival rate, lung cancer therapeutic outcomes remain unsatisfactory and still is a leading cause of cancer death. Metastasis and treatment resistance hampers the survival of lung cancer patients. Lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Our studies showed that LDOC1 strongly inhibits human LUAD A549 cells invasiveness and LDOC1 knockdown (KD) sensitized A549 cells to cisplatin. The mechanisms have not been fully elucidated.Coimmunoprecipitation-western blot and confocal microscopic analysis demonstrated the interaction between LDOC1 and the E3 ubiquitin ligase RNF40. RNF40 and its paralog RNF20 forms a heterodimer to monoubiquitylate histone H2B on lysine 120. H2B monoubiquitination (H2Bub1) is a prominent epigenetic mark involved in a variety of cellular processes mainly by regulating the transcription of specific gene sets. Our results showed that LDOC1 negatively regulates H2Bub1 in cell lines and specimens of LUAD. The regulatory mechanism may involve the proteasome degradation of H2B and nuclear translocation of RNF40 mediated by LDOC1. Microarray analysis revealed LDOC1 KD caused a global change in gene expression. SLC7A11, which encodes a cystine-glutamate antiporter, is a key component of ferroptosis epigenetically regulated by H2Bub1 and is significantly upregulated in LDOC1-deficient A549 cells, supporting that the increased H2Bub1 level is the cause of transcriptome reprogram triggered by LDOC1 KD. The IPA results and GEPIA database suggested nine genes upregulated by LDOC1 KD were lethal metastasis gene (LM) candidates with their high expression is associated with shorter overall survival of LUAD patients. Genes involved in inhibition of idiopathic pulmonary fibrosis signaling and upregulated in LDOC1 KD cells will be considered as cisplatin-responsive (CS) gene candidates regulated by LDOC1/H2Bub1 axis.We hypothesized that LDOC1 epigenetically affects tumor metastasis and chemotherapy efficacy of LUAD via regulation of H2Bub1. We aimed to meta-analysis the gene expression array data and chromatin immunoprecipitation (ChIP)-sequencing data to identify lethal-metastasis (LM) and cisplatin-responsive (CR) genes that regulated by LDOC1/H2Bub1 axis in LUAD.

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Gene expression profile at single cell level of cerebrospinal fluid (CSF) cells from lung adenocarcinoma leptomeningeal metastases patients (LUAD LM)

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