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Maintaining Human Glioblastoma Cellular Diversity Ex vivo using Three-Dimensional Organoid Culture
Published on: August 25, 2022
PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype
Shunlei Duan1, Guohong Yuan1, Xiaomeng Liu2
1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.
Insights
Loss of PTEN tumor suppressor function transforms neural stem cells into aggressive glioblastoma. Upregulation of PAX7 drives this transformation, offering a target for new cancer therapies.
Area of Science:
- Oncology
- Stem Cell Biology
- Molecular Biology
Background:
- PTEN is a critical tumor suppressor gene frequently altered in various cancers.
- Neural stem cells (NSCs) are susceptible to neoplastic transformation when PTEN is disrupted.
- Mesenchymal stem cells (MSCs) are resistant to PTEN-targeted neoplastic transformation.
Purpose of the Study:
- To investigate the role of PTEN in neural stem cell transformation.
- To elucidate the molecular mechanisms underlying PTEN-deficient NSC oncogenesis.
- To identify potential therapeutic targets for PTEN-mutated glioblastoma.
Main Methods:
- Targeted disruption of PTEN in human NSCs and MSCs.
- Analysis of metabolic and gene expression profiles in PTEN-deficient NSCs.
- In vivo tumor generation in immunodeficient mice.
- Investigation of PTEN-PAX7 interaction in the nucleus using ChIP assays.
- Clinical database analysis of PAX7 levels in glioblastoma.
- Assessment of mitomycin C sensitivity in PTEN-deficient NSCs.
Main Results:
- PTEN disruption induced neoplastic transformation and intracranial tumor formation in NSCs, but not MSCs.
- PTEN deficiency led to metabolic and gene expression changes indicative of neoplasia.
- PTEN normally inhibits PAX7 transcription in the nucleus via interaction with CREB/CBP.
- PTEN loss resulted in PAX7 upregulation, promoting NSC oncogenic transformation and glioblastoma aggressiveness.
- Increased PAX7 levels were observed in PTEN-deficient glioblastoma patient samples.
- Mitomycin C selectively induced apoptosis in PTEN-deficient NSCs.
Conclusions:
- PTEN acts as a crucial safeguard for NSCs, preventing transformation by inhibiting PAX7.
- PAX7 upregulation is a key driver of oncogenic transformation in PTEN-deficient NSCs.
- This study establishes a cellular model for investigating NSC transformation and identifies a potential therapeutic strategy targeting PTEN-deficient glioblastomas.
