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GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma
Inès C N Avenel1,2,3, Jesper D Ewald4,5, Jérémy Ariey-Bonnet3,6
1Department of Pathology, Bartholin Institute, Rigshospitalet, Copenhagen, Denmark.
Abstract:
Glioblastoma is the most common primary brain tumor in adults, characterized by an inherent aggressivity and resistance to treatment leading to poor prognoses. While some resistance mechanisms have been elucidated, a deeper understanding of these mechanisms is needed to increase therapeutic efficacy. In this study we first discovered glial-cell derived neurotrophic factor (GDNF) to be upregulated in patient-derived glioblastoma spheroid cultures after chemotherapeutic temozolomide treatment, through RNA-Seq experiments. Therefore, we investigated the role of the GDNF/GDNF receptor alpha 1 (GFRA1) signaling pathway as a resistance mechanism to chemotherapy with temozolomide and lomustine, as well as irradiation using patient-derived glioblastoma spheroid cultures. With qPCR experiments we showed a consistent upregulation of GDNF and its primary receptor GFRA1 following all three lines of treatment. Moreover, CRISPR/Cas9 knock-outs of GDNF in two patient-derived models sensitized these cells to chemotherapy treatment, but not radiotherapy. The increased sensitivity was completely reversed by the addition of exogeneous GDNF, confirming the key role of this factor in chemoresistance. Finally, a CRISPR KO of GFRA1 demonstrated a similar increased sensitivity to temozolomide and lomustine treatment, as well as radiotherapy. Together, our findings support the role of the GDNF/GFRA1 signaling pathway in glioblastoma chemo and radioresistance.
Insights
Glial-cell derived neurotrophic factor (GDNF) and its receptor GFRA1 promote glioblastoma resistance to chemotherapy and radiotherapy. Targeting this pathway could improve treatment efficacy for this aggressive brain tumor.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma is an aggressive primary brain tumor with poor prognosis.
- Mechanisms of glioblastoma treatment resistance require further elucidation to improve therapeutic outcomes.
Purpose of the Study:
- To investigate the role of the glial-cell derived neurotrophic factor (GDNF)/GDNF receptor alpha 1 (GFRA1) signaling pathway in glioblastoma resistance.
- To determine if GDNF/GFRA1 signaling mediates resistance to temozolomide, lomustine, and irradiation.
Main Methods:
- Utilized patient-derived glioblastoma spheroid cultures.
- Employed RNA-Sequencing (RNA-Seq) to identify upregulated genes post-treatment.
- Performed quantitative Polymerase Chain Reaction (qPCR) to confirm gene expression.
- Generated CRISPR/Cas9 knock-out models for GDNF and GFRA1.
Main Results:
- GDNF and GFRA1 were consistently upregulated in glioblastoma spheroids after temozolomide, lomustine, or irradiation treatment.
- GDNF knock-out sensitized glioblastoma cells to chemotherapy but not radiotherapy.
- GFRA1 knock-out sensitized cells to both chemotherapy and radiotherapy.
- Exogenous GDNF addition reversed the chemosensitization observed in GDNF knock-out models.
Conclusions:
- The GDNF/GFRA1 signaling pathway is a key mechanism contributing to glioblastoma chemoresistance.
- GDNF/GFRA1 signaling also plays a role in radioresistance.
- Targeting the GDNF/GFRA1 pathway presents a potential strategy to overcome glioblastoma treatment resistance.
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