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Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas
Jie Li1, Zachary J Taich1, Amit Goyal2
1Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego. Contributed equally to this work.
Abstract:
The intrinsic signaling cascades and cell states associated with the Glioma CpG Island Methylator Phenotype (G-CIMP) remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that G-CIMP+ tumors harbor decreased EGFR signaling using three independent datasets, including the Chinese Glioma Genome Atlas(CGGA; n=155), the REMBRANDT dataset (n=288), and The Cancer Genome Atlas (TCGA; n=406). Additionally, an independent collection of 25 fresh-frozen glioblastomas confirmed lowered pERK levels in G-CIMP+ specimens (p<0.001), indicating suppressed EGFR signaling. Analysis of TCGA glioblastomas revealed that G-CIMP+ glioblastomas harbored lowered mRNA levels for EGFR and H-Ras. Induction of G-CIMP+ state by exogenous expression of a mutated isocitrate dehydrogenase 1, IDH1-R132H, suppressed EGFR and H-Ras protein expression as well as pERK accumulation in independent glioblastoma models. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. The IDH1-R132H expression-induced pERK suppression can be reversed by exogenous expression of H-RasG12V. Finally, the G-CIMP+ Ink4a-Arf-/- EGFRvIII glioblastoma line was more resistant to the EGFR inhibitor, Gefitinib, relative to its isogenic G-CIMP- counterpart. These results suggest that G-CIMP epigenetically regulates EGFR signaling and serves as a predictive biomarker for EGFR inhibitors in glioblastoma patients.
Insights
The Glioma CpG Island Methylator Phenotype (G-CIMP) epigenetically suppresses EGFR signaling in glioblastoma. This G-CIMP state may predict patient response to EGFR inhibitors, offering new therapeutic strategies.
Area of Science:
- Molecular Oncology
- Epigenetics
- Cancer Signaling Pathways
Background:
- The Glioma CpG Island Methylator Phenotype (G-CIMP) is a distinct molecular subtype of glioblastoma.
- The precise signaling cascades and cell states regulated by G-CIMP are not well understood.
- Epidermal Growth Factor Receptor (EGFR) signaling is a critical pathway in glioblastoma development and progression.
Purpose of the Study:
- To investigate the relationship between the G-CIMP phenotype and EGFR signaling in glioblastoma.
- To determine the epigenetic mechanisms underlying G-CIMP-mediated regulation of EGFR signaling.
- To evaluate the potential of G-CIMP as a predictive biomarker for EGFR-targeted therapies.
Main Methods:
- Analysis of EGFR signaling using mRNA signatures across multiple independent glioblastoma datasets (CGGA, REMBRANDT, TCGA).
- Validation of suppressed EGFR signaling markers (pERK, EGFR, H-Ras) in G-CIMP+ glioblastomas.
- Experimental induction of G-CIMP state via mutated isocitrate dehydrogenase 1 (IDH1-R132H) expression and assessment of epigenetic modifications (H3K9me3, H3K27me3) at target gene promoters.
Main Results:
- G-CIMP+ glioblastoma tumors consistently exhibited decreased EGFR signaling across independent patient cohorts.
- IDH1-R132H expression induced the G-CIMP+ state, suppressing EGFR and H-Ras expression and pERK accumulation.
- Epigenetic analysis revealed increased repressive histone marks (H3K9me3, H3K27me3) at EGFR and H-Ras promoters in G-CIMP+ cells.
- G-CIMP+ glioblastoma cells showed resistance to the EGFR inhibitor Gefitinib, unlike their G-CIMP- counterparts.
Conclusions:
- The G-CIMP phenotype epigenetically suppresses EGFR signaling in glioblastoma.
- G-CIMP acts as a potential predictive biomarker for response to EGFR inhibitors in glioblastoma patients.
- Targeting epigenetic regulation in G-CIMP+ glioblastomas may offer novel therapeutic avenues.
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