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Phenotypic states of leptomeningeal metastasis

ABSTRACT: Leptomeningeal metastasis (LM), or spread of cancer cells into the cerebrospinal fluid, is characterized by a rapid onset of debilitating neurological symptoms and markedly bleak prognosis. The lack of reproducible in vitro and in vivo models has prevented development of novel, LM-specific therapies. Although LM allows for longitudinal sampling of floating cancer cells with a spinal tap, attempts to culture patient-derived leptomeningeal cancer cells have not been successful. We therefore employ leptomeningeal derivatives of human breast and lung cancer cell lines that reproduce both floating and adherent phenotypes of human LM in vivo and in vitro. We introduce a trypsin/EDTA-based fractionation method to reliably separate the two cell subsets and demonstrate that in vitro cultured floating cells have decreased proliferation rate, lower ATP content, and are enriched in distinct metabolic signatures. Long-term fractionation and transcriptomic analysis suggest a high degree plasticity between the two phenotypes in vitro. Floating cells colonize mouse leptomeninges more rapidly and associate with shortened survival. In addition, patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI-positive) disease. Together, these data support mechanistic evidence of a metabolic adaptation that allows cancer cells to thrive in their natural environment but leads to death in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137020 | GEO | 2020/01/21

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.

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Phenotypic states of leptomeningeal metastasis

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