Abstract
Diffusely infiltrating gliomas (DIGs) are difficult to completely resect and are associated with a high rate of tumor relapse and progression from low- to high-grade glioma. In particular, optimized short-term culture-enriching patient-derived glioma stem cells (GSCs) are essential for customizing the therapeutic strategy based on clinically feasible in vitro drug screening for a wide range of DIGs, owing to the high inter-tumoral heterogeneity. Herein, we constructed a novel high-throughput culture condition screening platform called ‘GFSCAN’, which evaluated the cellular growth rates of GSCs for each DIG sample in 132 serum-free combinations, using 13 previously reported growth factors closely associated with glioma aggressiveness. In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype. GSCs were clustered according to the dependency on epidermal growth factor and basic fibroblast growth factor (E&F), and isocitrate dehydrogenase 1 (IDH1) wild-type GSCs showed higher E&F dependencies than IDH1 mutant GSCs. More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&F, which could be an aid in clinical decision-making for these DIGs. Thus, we demonstrated the utility of GFSCAN in personalizing in vitro cultivation to nominate personalized therapeutic options, in a clinically relevant time frame, for individual DIG patients, where standard clinical options have been exhausted.
Highlights
Infiltrating gliomas (DIGs) are categorized by the World Health Organization (WHO)into diffuse astrocytomas, oligodendrogliomas, and isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant and wild-type glioblastomas, according to their histological grades, IDH1/2 status, and chromosome arm 1p and 19q (1p19q) co-deletion [1,2]
Benjamini q value ≤ 0.1). (D) The cell growth index of IDH1-mut and -wt glioma stem cells (GSCs) in neural basal medium basal medium supplemented with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) (NBE) (p = 0.0027). (E) The gene-set enrichment supplemented with plot
To improve culture conditions for IDH1-mut GSCs with specific mutations, we examined the association between the genomic mutations and cell growth indices of all growth factor combinations in IDH1-mut GSCs (Figure 5C)
Summary
Into diffuse astrocytomas, oligodendrogliomas, and isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant (mut) and wild-type (wt) glioblastomas, according to their histological grades, IDH1/2 status, and chromosome arm 1p and 19q (1p19q) co-deletion [1,2]. DIGs are among the most devastating tumor types and are characterized by extensive infiltrative growth, a low probability of complete resection, and resistance to combined therapies [3,4]. Diffuse astrocytomas (IDH mutant and 1p19q intact) and oligodendrogliomas (IDH mutant and 1p19q co-deleted) belong to WHO grades II and III, which represent "lower-grade gliomas" (LGGs) in The Cancer Genome Atlas (TCGA) [1,2,3,4]. Organoid culture methods have definite advantages in mimicking the in vivo microenvironment and biological complexities of original tumors [8], but the two-dimensional (2D) spheroid culture system is still preferred as it is more reproducible, flexible and suitable for elucidating cancer drug responses and, in particular, the response of glioma stem cells (GSCs) with a high-throughput large scale [9,10,11] compared to other
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