Single-cell RNA-seq reveals diverse molecular signatures associated with Methotrexate resistance in primary central nervous system lymphoma cells.

in Journal of neuro-oncology by Rosuke Osako, Azusa Hayano, Atsushi Kawaguchi, Ryuya Yamanaka

TLDR

  • The study used single-cell sequence analysis to identify key genes and signaling pathways related to methotrexate resistance in PCNSL and discovered a potential candidate drug, cyclosporine A, for treatment of methotrexate-resistant cells.
  • The findings may improve our understanding of treatment responses and provide new therapeutic strategies for patients with PCNSL.

Abstract

Methotrexate is one of the most essential single agents in patients with primary central nervous system lymphoma (PCNSL). However, 25-50% result in relapse with a poor prognosis. Therefore, studies on methotrexate resistance are warranted to explore salvage chemotherapy for recurrent PCNSL. Single-cell sequence analysis enables the characterization of novel cell types and provides a precise understanding of cancer biology. Single-cell sequence analysis of parental and methotrexate-resistant PCNSL cells was performed. We used a Weighted Gene Co-expression Network Analysis to identify groups of significantly connected genes. We identified consensus modules in both the HKBML and TK datasets. HLA-DRβ1, HLA-DQβ1,and SNRPG were hub genes those detected in both datasets revealed by network analysis. Cyclosporine A was selected as the candidate drug for treating methotrexate-resistant cells. The results of the present study characterized the methotrexate resistance-related signaling pathways in cultured PCNSL cells. Overall, these results may account for variations in treatment responses and lead potential novel therapeutic strategies for patients with PCNSL.

Overview

  • The study focused on investigating methotrexate resistance in primary central nervous system lymphoma (PCNSL) to explore salvage chemotherapy options.
  • Single-cell sequence analysis was used to identify novel cell types and characterize cancer biology in parental and methotrexate-resistant PCNSL cells.
  • The study aimed to identify key genes and signaling pathways related to methotrexate resistance and discover potential candidate drugs for treatment.

Comparative Analysis & Findings

  • Single-cell sequence analysis identified several hub genes, including HLA-DRβ1, HLA-DQβ1, and SNRPG, that were common to both parental and methotrexate-resistant PCNSL cells.
  • Weighted Gene Co-expression Network Analysis revealed consensus modules in both datasets, suggesting a common underlying biological mechanism.
  • Cyclosporine A was identified as a potential candidate drug for treating methotrexate-resistant PCNSL cells based on the study's findings.

Implications and Future Directions

  • The study's findings may explain variations in treatment responses and provide new insights into methotrexate resistance mechanisms.
  • Future studies could explore the role of identified hub genes and pathways in methotrexate resistance and their potential as therapeutic targets.
  • Clinical trials may be warranted to evaluate the effectiveness of identified candidate drugs, such as cyclosporine A, in treating methotrexate-resistant PCNSL patients.
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