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distribution limits the ability of organoid models to fully tumorigenesis. This model mimics tumor invasiveness
simulate the real tumor growth environment. Jacob and allows for drug effect assessment in the context of
et al. further optimized the GBM sample processing specific DNA mutations (Figure 3A). The GLICO (glioma
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method, reducing clonal selection and generating highly organoid coculture) model maintains patient-specific
faithful GBM organoids with a success rate of 91.4%. EGFR amplification and phosphorylated RTK signaling,
These GBOs are highly similar to the original tumors in with spontaneous tumor microtubule formation closely
terms of somatic mutations and copy number variation resembling in situ tumors. This makes GLICO a valuable
analysis, accurately reflecting the tumor’s genotypic and tool for studying GBM invasion and the TME. Jacob et al.
phenotypic heterogeneity. These optimizations greatly established a patient-derived GBO model that captures
enhance the accuracy of organoid models in simulating tumor heterogeneity and has been used to test personalized
the heterogeneity of GBM, increasing their effectiveness as therapies, including radiation, temozolomide, and targeted
research models. drugs (Figure 3B). 113
4.2.2.2. GLICO model In a study of Grade II astrocytoma patients, the GLICO
model predicted tumor progression to Grade IV GBM,
Cocultivation of BOs with GBM is rapidly becoming an which was clinically validated after an 18-month follow-up
effective tool for studying tumor invasion and tumor-normal (Figure 3C). This highlights the model’s potential for early
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cell interactions. This method recreates the interactions screening and disease progression prediction. CRISPR/
between tumor-host cells and their relationship with the 3D Cas9 has also been used to induce GBM in BOs by targeting
ECM by coculturing pluripotent stem cell-derived BOs with cancer-related genes. Ogawa et al. 118 created a TP53-
human GSCs in a 3D environment. 111,112 The cocultivation knockout model with increased proliferation markers,
model not only simulates the process of tumor invasion while Bian et al. developed models with distinct genetic
but also helps researchers explore the complex interactions alterations to mimic specific tumor features. These studies
between tumor cells and healthy brain cells. The “GLICO” replicated GBM development from various mutations and
(cerebral organoid glioma) model developed by Linkous uncover mechanisms of glial cell differentiation, identifying
et al. combines patient-derived GSCs with hESC-derived mutational combinations leading to GBM and CNS-PNET-
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BOs, providing a reverse-engineering approach to study like tumors.
patient-specific GBM (Figure 1). Compared to traditional
2D cultures, GBM organoids (GBOs), and PDX models, 5. Organoids in PD
the GLICO model shows higher relevance to the primary
tumor at multiple levels. This relevance is reflected in 5.1. Structure and microenvironment of PD
transcriptomic similarity, diversity of cellular states, 5.1.1. Overview of NDDs
stemness characteristics, and strong invasiveness. 114 NDDs pose a significant challenge to global health,

4.3. Practical applications of organoids in GBM characterized by the progressive degeneration of specific
neuronal populations and the loss of normal brain
GBM is the most common and aggressive primary brain function. Aging, genetic factors, protein misfolding,
tumor, with a high degree of malignancy. Most GBMs and programmed cell death are key contributors to
rapidly transform from normal brain cells, while about NDDs. Molecularly, the pathology of NDDs often
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10% progress from lower-grade astrocytoma. The current involves the accumulation of abnormal proteins in
treatments, including surgical resection, radiation neurons and glial cells, with the type of protein and
therapy, and chemotherapy, temporarily suppress tumor the location of accumulation in the brain determining
progression but fail to prevent high recurrence rates. Even the clinical presentation of the disease. For instance,
with aggressive management, the 5-year survival rate the abnormal accumulation of amyloid-beta and tau
remains low at 3 – 7%. 115 proteins in Alzheimer’s disease or alpha-synuclein in PD
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To model GBM, BOs are cocultured with fluorescently leads to neuronal dysfunction. Although progress has
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labeled GSCs to promote tumor growth. Linkous et al. been made in understanding the mechanisms of NDDs,
successfully created a GBM model by coculturing labeled effective disease-modifying therapies are still lacking.
GSCs with BOs for 24 hours, allowing the stem cells to
be fully engulfed. Within a week, the organoids exhibit 5.1.2. Cellular and molecular basis of PD
GBM neuropathological characteristics through GFAP PD is a prevalent chronic neurodegenerative disorder
immunofluorescence staining, with tumor cells showing that primarily affects motor functions. Its pathological
deep invasion and proliferation. Similarly, Bian et al. 118 hallmarks include the formation of Lewy bodies, composed
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developed the neoCOR model, using CRISPR/Cas9 of insoluble aggregates of α-synuclein, and the degeneration
to introduce oncogenic mutations and simulate brain of dopaminergic neurons in the substantia nigra. The early
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Volume 1 Issue 1 (2025) 9 doi: 10.36922/or.8261