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Updated: Sep 21, 2025
Co-culture of Glioblastoma Stem-like Cells on Patterned Neurons to Study Migration and Cellular Interactions
Published on: February 24, 2021
Glioma progression is shaped by genetic evolution and microenvironment interactions
Frederick S Varn1, Kevin C Johnson1, Jan Martinek1
1The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Abstract:
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.
Insights
Understanding diffuse glioma recurrence requires analyzing genetic and cellular changes. IDH-mutant and IDH-wild-type tumors show distinct progression patterns, offering potential therapeutic targets.
Area of Science:
- Neuro-oncology
- Cancer Genomics
- Tumor Microenvironment
Background:
- Therapy resistance in diffuse glioma is a significant clinical challenge.
- The cellular and genetic factors driving treatment resistance remain poorly understood.
Purpose of the Study:
- To identify treatment-associated cellular and genetic alterations in recurrent diffuse gliomas.
- To compare recurrence patterns between isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma subtypes.
Main Methods:
- Analysis of RNA and/or DNA sequencing data from paired tumor samples of 304 adult patients.
- Assessment of histological features, somatic alterations, and microenvironment interactions at recurrence.
Main Results:
- Recurrence patterns differed based on IDH mutation status, involving histological changes, genetic alterations, and microenvironment interactions.
- Hypermutation and CDKN2A deletions correlated with increased proliferation in both subtypes.
- IDH-wild-type tumors showed increased invasiveness and neuronal signaling, suggesting a role in progression.
- Mesenchymal transition was linked to myeloid cell interactions with neoplastic cells.
Conclusions:
- Distinct recurrence phenotypes in diffuse glioma are IDH-dependent and involve cellular, genetic, and microenvironmental factors.
- These recurrence-associated phenotypes present potential therapeutic targets for altering disease progression.
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