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| Status |
Public on Feb 13, 2024 |
| Title |
GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glioblastoma (GBM) 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 (TMZ) 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.
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| Overall design |
To uncover potential genes of interest in glioblastoma treatment resistance we used 3 patient-derived primary glioblastoma cell lines, treated each one with either the alkylating agent Temozolomide or a DMSO control and compared control/post treatment gene expression through an RNA-Seq experiment.
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no raw files due to patient privacy issues (RNASeq experiment was done on patient-derived samples)
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| Contributor(s) |
Mark B, Martin T, Mads T |
| Citation(s) |
39085346 |
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| Submission date |
Feb 12, 2024 |
| Last update date |
Aug 26, 2024 |
| Contact name |
Inès CN Avenel |
| E-mail(s) |
ines.clemence.nati.avenel@regionh.dk
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| Organization name |
BRIC
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| Street address |
Ole Maaløes Vej 5
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| City |
København Nv |
| ZIP/Postal code |
2200 |
| Country |
Denmark |
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| Platforms (1) |
| GPL18460 |
Illumina HiSeq 1500 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1075663 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE255581_TMZ_RNAseq_cpm_matrix.xlsx |
1.3 Mb |
(ftp)(http) |
XLSX |
| GSE255581_processed_file_-_other_format.txt.gz |
539.8 Kb |
(ftp)(http) |
TXT |
| Raw data not provided for this record |
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