EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors
Li Li1, Amalia Dutra, Evgenia Pak
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Abstract:
Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.
Insights
Combining epidermal growth factor receptor (EGFR) activation with PTEN loss in neural cells promotes glioblastoma formation. This genetic combination drives tumor growth, genomic instability, and resistance to DNA damage, offering insights into brain tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastomas frequently exhibit activated epidermal growth factor receptor (EGFR) and loss of the PTEN tumor suppressor.
- The synergistic role of these genetic alterations in cellular transformation remains unclear.
Purpose of the Study:
- To investigate the combined effect of EGFRvIII expression and PTEN loss on neural precursor cell transformation.
- To elucidate the molecular mechanisms underlying tumor formation and genomic instability induced by these genetic lesions.
Main Methods:
- PTEN-deficient neural precursor cells were infected with a retrovirus encoding EGFRvIII.
- Characterization of transformed cells included assessments of proliferation, self-renewal, stem cell marker expression, DNA damage response, and pathway activation (RAS/ERK, PI3K/Akt).
- Tumorigenicity and genomic stability were evaluated in vivo, including analysis of chromosomal aberrations.
Main Results:
- EGFRvIII expression in PTEN-deficient cells resulted in highly mitotic tumors with glioblastoma markers.
- Transformed cells displayed increased proliferation, stemness (CD133 expression), resistance to oxidative stress and radiation, and activation of RAS/ERK and PI3K/Akt pathways.
- Akt-mediated phosphorylation of Chk1 by EGFRvIII/PTEN loss suppressed DNA damage response, while tumor growth in mice led to secondary chromosomal aberrations and increased invasiveness.
Conclusions:
- The co-occurrence of EGFR activation and PTEN loss provides a molecular basis for glioblastoma development.
- This combination of genetic lesions induces significant genomic instability, contributing to tumor progression and invasiveness.
- The findings highlight the critical role of these mutations in driving aggressive brain tumor phenotypes and suggest therapeutic targets.
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