Role of CARM1 in Glioblastoma

ABSTRACT: One driving factor of Glioblastoma (GBM) heterogeneity and therapy resistance is the capacity of glioma stem-like cells (GSCs) to hijack developmental signaling programs. However, it remains unclear how glioma stem-like cells regulate many of their developmental signaling pathways and how these pathways might be therapeutically exploited. The arginine methyltransferase, CARM1, has been shown to play critical roles in maintaining stem cell pluripotency, preventing differentiation, and recently has been found to be upregulated in Glioblastoma. To date, there is little to no understanding of what role CARM1 plays in regulating developmental processes in Glioblastoma. To address this gap in knowledge, we use a multi-omics approach to characterize which developmental processes are specifically regulated by CARM1 in GSCs. We find that loss of CARM1 results in dysregulation of several developmental markers: ARX, GFAP, NGFR, PDGFRA and results in both a proteomic and transcriptomic shift towards the radial glia cell lineage. Moreover, CARM1 KO cells develop an increased survival dependency on NGFR/NTRK signaling and are hypersensitive to the FDA approved brain penetrant NTRK inhibitor, Entrectinib. Mechanistically, we find that NFIA is a CARM1 substrate and can repress NGFR signaling just as CARM1 does, and thus the CARM1/NFIA relationship is likely a key regulator of NGFR/NTRK signaling in GSCs. Altogether, we demonstrate that CARM1 regulates the cell lineage of GSCs at the transcriptomic/proteomic level, likely driven by CARM1 dependent NFIA methylation, and creates a therapeutic vulnerability to NTRK inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292789 | GEO | 2026/03/29

REPOSITORIES: GEO