GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma

Inès C N Avenel, Jesper D Ewald, Jérémy Ariey-Bonnet, Ida H Kristensen, Stine A Petterson, Martin N Thesbjerg, Mark Burton, Mads Thomassen, Krister Wennerberg, Signe R Michaelsen, Bjarne W Kristensen*

*Corresponding author for this work

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.

Original languageEnglish
Article number17639
JournalScientific Reports
Volume14
Issue number1
Pages (from-to)17639
ISSN2045-2322
DOIs
Publication statusPublished - 31 Jul 2024

Keywords

  • Glioblastoma/metabolism
  • Humans
  • Glial Cell Line-Derived Neurotrophic Factor/metabolism
  • Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism
  • Drug Resistance, Neoplasm/genetics
  • Signal Transduction
  • Temozolomide/pharmacology
  • Radiation Tolerance/genetics
  • Brain Neoplasms/genetics
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic/drug effects
  • Lomustine/pharmacology
  • Spheroids, Cellular/metabolism

Fingerprint

Dive into the research topics of 'GDNF/GFRA1 signaling contributes to chemo- and radioresistance in glioblastoma'. Together they form a unique fingerprint.

Cite this