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Depletion of CARM1 slows in-vivo tumorigenicity and rewires developmental programming in Glioma stem-like cells

ABSTRACT: Glioma stem-like cells (GSCs) exploit developmental signaling programs that contribute to glioblastoma heterogeneity and therapy resistance. Here, we define a role for the arginine methyltransferase CARM1 in regulating GSC lineage state and survival signaling. CARM1 depletion slows GSC growth, increases apoptosis, alters histone post-translational modifications, and shifts transcriptomic and proteomic profiles toward a radial glial-like state. Loss of CARM1 increases NGFR/NTRK signaling and sensitizes GSCs to NTRK and AKT inhibition. Mechanistically, NFIA is a CARM1 substrate, and mutation of NFIA arginine 389 increases NGFR expression, supporting a role for CARM1-dependent NFIA methylation in NGFR repression. In orthotopic xenografts, CARM1 depletion reduces tumor burden and prolongs survival. These findings identify CARM1 as a regulator of GSC developmental programs and NGFR/NTRK-dependent survival.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD080227 | Pride | 2026-06-28

REPOSITORIES: Pride

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			Action	DRS
	20240529_Dejauwne_1FO_NSC11_Scr_Fullproteome_rep_5_6-7-2024_02-58-37_PSE-25cm-150um-1p5um_45min_700nl_5mmTrap_20umEmitter_v1_Slot1-42_1_1264.mzML	Mzml
	20240529_Dejauwne_1F_NSC11_Scr_Fullproteome_rep_1_6-6-2024_22-32-10_PSE-25cm-150um-1p5um_45min_700nl_5mmTrap_20umEmitter_v1_Slot1-89_1_1260.mzML	Mzml
	20240529_Dejauwne_1F_NSC11_Scr_Fullproteome_rep_2_6-6-2024_23-38-43_PSE-25cm-150um-1p5um_45min_700nl_5mmTrap_20umEmitter_v1_Slot1-06_1_1261.mzML	Mzml
	20240529_Dejauwne_1F_NSC11_Scr_Fullproteome_rep_3_6-7-2024_00-45-17_PSE-25cm-150um-1p5um_45min_700nl_5mmTrap_20umEmitter_v1_Slot1-18_1_1262.mzML	Mzml
	20240529_Dejauwne_1F_NSC11_Scr_Fullproteome_rep_4_6-7-2024_01-51-59_PSE-25cm-150um-1p5um_45min_700nl_5mmTrap_20umEmitter_v1_Slot1-30_1_1263.mzML	Mzml

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Project description:Glioma-derived stem-like cells (GSCs) are hypothesized to provide a repository of cells in tumors that can self-replicate and be resistant to radiation and chemotherapeutic agents developed for the treatment of tumors. The potential lack of response of GSCs to traditional cytotoxic and radiation therapies has significant implications for tumor biology and therapeutics. At M.D. Anderson Cancer Center, a large number of GSC lines representing several glioma sub-types have been isolated and characterized with respect to gene expression. In order to identify potential therapeutic targets relating to GSC phenotype, we examined protein expression in 35 GSC lines relative to an external protein standard using label-free quantitative proteomics. Samples were analyzed in triplicate by nanoLC-MS/MS (Orbitrap Elite, Thermo) in block-randomized groups of three GSCs plus the external standard. The resulting .raw files were aligned by group in Progenesis LC-MS (Nonlinear Dynamics). Database searching was performed with PEAKS 6 software (BSI) against a UniprotKB/SwissProt Human database appended with the cRAP contaminant database. Peptide intensities were exported for analysis in DanteR. The resulting relative fold changes were used to drive unsupervised hierarchical clustering of the cell lines for the purpose of classifying cell lines, and Ingenuity Pathway Analysis (IPA) and the DAVID webtool were used to determine the biochemical pathways and biological processes impacted by protein changes in each cell line. Within IPA, Upstream Analysis was used to predict biological functions and transcriptional regulators whose increased or decreased activity was consistent with the observed fold changes, and the resulting upstream regulators with significant z-scores were exported for unsupervised hierarchical clustering. In addition to showing upstream regulators known to be associated with glioma, including Myc, tumor protein 53 (TP53), N-myc proto-oncogene protein (MYCN), two novel upstream regulators, synoviolin 1 (SYVN1) and interleukin 5 (IL5) were identified. A cluster of proteins found to be decreased relative to mixed control in mesenchymal cell lines was subjected to further bioinformatics analysis, identifying SRSF2 as a potential upstream regulator.

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Depletion of CARM1 slows in-vivo tumorigenicity and rewires developmental programming in Glioma stem-like cells

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