Impact of METTL1 in Glioblastoma development and intratumoral immune response
Aurora Campos
Centro de Investigación del Cáncer (Universidad de Salamanca-CSIC)
Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor, characterized by poor prognosis and limited treatment options. One of the primary obstacles to effective treatment is its heterogenous and highly immunosuppressive tumor microenvironment. Emerging evidence highlights the critical role of RNA modifications in regulating gene expression during both normal development and tumorigenesis. In this context, the tRNA methyltransferase METTL1 has gained attention as a potential oncogenic driver and specially functions as a key modulator of intratumoral immune evasion.
Our research shows that METTL1 is significantly overexpressed in GBM, particularly in mesenchymal subtypes, and in within glioma stem cells, key contributors to therapeutic resistance and tumor recurrence. By performing functional loss-of-function studies we find that METTL1 depletion in GBM cells reduces tumor proliferation and enhances sensitivity to temozolomide. To investigate its role in GBM progression in vivo, we employed a preclinical mouse model combining the RCAS-TVA and CRISPR-Cas9 systems. This strategy allows in vivo gene editing to induce glioblastoma formation in mouse models. We found that Mettl1 loss significantly impairs tumor progression with lower incidence and reduced tumor burden. This effect is associated with a more cytotoxic tumor microenvironment, characterized by increased M1-like macrophages polarization and reduced microglia infiltration. Besides, METTL1 knockout led to a reduction in T regulatory cells and an increase in peritumoral CD8 + T cells number.
Together, these findings identify METTL1 as a critical regulator of GBM growth and immune suppression, supporting its potential as a therapeutic target for overcoming resistance and improving patient outcomes.