Patient-derived tumor organoids mimic treatment-induced DNA damage response in glioblastoma

Area of Science:

• Neuro-oncology
• Cancer Biology
• Translational Medicine

Background:

• Glioblastoma (GB) is the most common primary malignant brain tumor.
• GB is characterized by inherent therapy resistance, invasiveness, and heterogeneity.
• Preclinical in vitro models often fail to capture GB complexity.

Purpose of the Study:

• To investigate the therapeutic response of patient-derived glioblastoma organoids (GBOs) to standard treatment.
• To assess the utility of GBOs in modeling GB therapy resistance.
• To explore the molecular mechanisms underlying treatment response in GBOs.

Main Methods:

• Generation of patient-derived glioblastoma organoids (GBOs).
• Treatment of GBOs with standard therapy (irradiation and temozolomide).
• Analysis of GBO viability, invasion, and molecular markers (gene and protein levels).

Main Results:

• Standard therapy showed no significant effect on GBO viability or invasion.
• Upregulation of E3 ubiquitin-protein ligase (MDM2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) was observed.
• Activation of the p53 pathway and DNA-damage response mechanisms (ATM, ATR) was confirmed.

Conclusions:

• GBOs effectively recapitulate glioblastoma therapy resistance observed in patients.
• GBOs serve as a valuable platform for assessing individual patient responses to therapy.
• GBOs facilitate further research into mechanisms of glioblastoma treatment resistance.