Translational study uncovers METTL1-driven tRNA m7G modification promoting breast cancer brain metastasis via TRADD translation, indicating a potential target for therapeutic intervention.
Key Points
To determine the mechanistic role of tRNA N(7)-methylguanosine (m7G) modification and METTL1 in breast cancer brain metastasis and tumor immune regulation.
Analyzed single-cell RNA-seq and bulk transcriptomic data from GEO and TCGA cohorts to evaluate m7G scores, immune microenvironment characteristics, and metastasis-free survival.
Profiled METTL1-mediated m7G tRNA modification levels using Trac-seq and evaluated translation efficiency alongside integrative codon-usage analysis.
Performed in vitro invasion assays, codon-mutation experiments, and in vivo mouse rescue models combining METTL1 pharmacological inhibition with TRADD overexpression.
Elevated m7G scores and high METTL1 expression correlated with an immunosuppressive microenvironment and significantly shortened brain metastasis–free survival.
METTL1-mediated tRNA m7G modification selectively enhanced translation efficiency of MAPK pathway genes, with TRADD showing the most significant increase.
Pharmacological inhibition of METTL1 suppressed breast cancer brain metastasis in vivo, whereas enforced TRADD overexpression partially rescued metastatic progression.