Back to Search Start Over

Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Authors :
Verduin M
Hoosemans L
Vanmechelen M
van Heumen M
Piepers JAF
Astuti G
Ackermans L
Schijns OEMG
Kampen KR
Tjan-Heijnen VCG
de Barbanson BA
Postma AA
Eekers DBP
Broen MPG
Beckervordersandforth J
Staňková K
de Smet F
Rich J
Hubert CG
Gimenez G
Chatterjee A
Hoeben A
Vooijs MA
Source :
Neuro-oncology advances [Neurooncol Adv] 2023 Nov 25; Vol. 5 (1), pp. vdad152. Date of Electronic Publication: 2023 Nov 25 (Print Publication: 2023).
Publication Year :
2023

Abstract

Background: Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance.<br />Methods: GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ.<br />Results: WES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect.<br />Conclusions: Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.<br />Competing Interests: None declared.<br /> (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Details

Language :
English
ISSN :
2632-2498
Volume :
5
Issue :
1
Database :
MEDLINE
Journal :
Neuro-oncology advances
Publication Type :
Academic Journal
Accession number :
38130902
Full Text :
https://doi.org/10.1093/noajnl/vdad152