Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
Yiwen Jiang1, Voichita Dana Marinescu1, Yuan Xie1
1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Abstract:
The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.
Insights
The origin of glioblastoma (GBM) cells impacts tumor development and drug response. GBMs from neural stem-like cells show faster growth and are less drug-resistant, unlike those from differentiated cells.
Area of Science:
- Neuroscience
- Cancer Biology
- Genetics
Background:
- The cell of origin for glioblastoma (GBM) is unknown, hindering understanding of disease progression and treatment outcomes.
- The phenotypic state of the initial transformed cell's influence on GBM development and properties requires further investigation.
Purpose of the Study:
- To investigate how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties.
- To identify a gene signature associated with GBM cell origin and apply it to patient-derived GC lines.
Main Methods:
- Induction of GBM in adult mice from cells with varying differentiation states (GFAP+, Nestin+, CNP+).
- Analysis of tumor development, GC properties, and drug resistance.
- Transcriptome analysis to identify a mouse cell origin (MCO) gene signature.
- Partitioning of 61 patient-derived human GC lines using the MCO gene signature.
Main Results:
- GBM induced in GFAP-expressing cells (neural stem-cell-like) exhibited accelerated tumor development and produced more malignant GCs (mGC1GFAP).
- mGC1GFAP cells were less resistant to cancer drugs compared to GCs originating from more differentiated cells (mGC2NES and mGC3CNP).
- Human GC lines clustering with mGC1GFAP showed increased self-renewal, tumorigenicity, and drug sensitivity compared to those clustering with more differentiated origins.
Conclusions:
- The cell of origin significantly influences GBM aggressiveness and drug sensitivity.
- A 196-gene MCO signature can classify human GBM cells, correlating with distinct biological behaviors and therapeutic vulnerabilities.
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