TY - JOUR
T1 - Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity
AU - Verduin, Maikel
AU - Hoosemans, Linde
AU - Vanmechelen, Maxime
AU - van Heumen, Mike
AU - Piepers, Jolanda A. F.
AU - Astuti, Galuh
AU - Ackermans, Linda
AU - Schijns, Olaf E. M. G.
AU - Kampen, Kim R.
AU - Tjan-Heijnen, Vivianne C. G.
AU - de Barbanson, Buys A.
AU - Postma, Alida A.
AU - Eekers, Danielle B. P.
AU - Broen, Martijn P. G.
AU - Beckervordersandforth, Jan
AU - Stankova, Katerina
AU - de Smet, Frederik
AU - Rich, Jeremy
AU - Hubert, Christopher G.
AU - Gimenez, Gregory
AU - Chatterjee, Aniruddha
AU - Hoeben, Ann
AU - Vooijs, Marc A.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.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.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.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.
AB - 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.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.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.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.
KW - glioblastoma
KW - organoids
KW - preclinical models
KW - temozolomide resistance
KW - tumor heterogeneity
KW - INTRATUMORAL HETEROGENEITY
KW - TEMOZOLOMIDE
KW - PATHWAYS
KW - SYSTEM
U2 - 10.1093/noajnl/vdad152
DO - 10.1093/noajnl/vdad152
M3 - Article
SN - 2632-2498
VL - 5
JO - Neuro-Oncology Advances
JF - Neuro-Oncology Advances
IS - 1
M1 - vdad152
ER -