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Discov Oncol
Discov Oncol
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2730-6011
Springer US New York

39292297
1346
10.1007/s12672-024-01346-w
Review
A reference for selecting an appropriate method for generating glioblastoma organoids from the application perspective
Liang Jing 1
He Peng hep6ng0806@swmu.edu.cn

2
1 https://ror.org/0014a0n68 grid.488387.8 Department of Operating Room, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan China
2 https://ror.org/0014a0n68 grid.488387.8 Department of Biobank, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan China
18 9 2024
18 9 2024
12 2024
15 45930 5 2024
12 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Glioblastoma organoids (GBOs) serve as a powerful and reliable tool to study glioblastoma stem cells (GSCs) and glioblastoma (GBM). GBOs can be derived from different materials using different methods. To identify the predominant generation methods and the most applications of GBOs, we searched four databases (PubMed, Embase, Web of Science, and Wiley Online Laboratory) from August 2021 to August 2023. After screening, 42 out of 295 articles were included and analyzed. GBOs in these articles were generated using only one material, such as tumor tissues, tumor cells, and gene-edited multifunctional stem cells, or simultaneously using two materials, such as tumor cells and normal organoids. Methodologically, direct cultivation of GBM cells or tissues was the most commonly used method to generate GBOs. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were the frequently used multifunctional stem cells to generate GBOs by simultaneously silencing P53, NF1, and PTEN using CRISPR/Cas9. In terms of applications, GBOs generated by direct cultivation of GBM tissue had the most applications, including molecular mechanisms, therapy, and culture technique. This review provides a theoretical reference for selecting an appropriate method to generate GBOs when studying GSCs and GBM.

Keywords

Glioblastoma
Glioblastoma organoids
Glioblastoma stem cells
Organoid
Cell culture
http://dx.doi.org/10.13039/501100004829 Science and Technology Department of Sichuan Province 2020JDRC013 issue-copyright-statement© Springer Science+Business Media, LLC 2024
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pmcIntroduction

Glioblastoma (GBM) is the most common primary brain tumor with the highest malignancy and worst prognosis [1, 2]. Despite the development of surgical resection and chemotherapy, there are no effective methods of prevention and cure. Less than 10% of patients with glioblastoma survive within five years of diagnosis [3]. Histologically, GBM tissues are composed of many heterogeneous cells produced from a subpopulation of self-renewing cells called GBM stem cells (GSCs). GSCs are considered the most critical factor in the development, progression, and recurrence of GBM [4]. Therefore, GSC research must contribute to understanding the molecular mechanisms of GBM and developing new strategies to cure it.

Cell culture is an essential technique for studying cellular properties and functions. Traditional two-dimensional (2D) cell culture system has several disadvantages. It lacks an intricate cellular microenvironment and a hierarchical structure of native tissues. Relatively, three-dimensional (3D) cell culture system mimics cellular growth environment, intercellular interactions, and hierarchical structure. Organoids are considered as 3D tissues generated from pluripotent stem cells or adult stem cells by mimicking human development or organ regeneration. Organoids can mimic the architecture and function of native tissues and can be cultured and propagated over long periods of time [5–7]. Thus, organoids can serve as a more powerful and reliable tool for biological studies of cancer and cancer stem cells, including GSCs. To date, many different types of organoids have been created and widely used in scientific research, such as brain organoids, liver organoids, kidney organoids, stomach organoids, and patient-derived organoids [8–11].

Organoids include two classes: normal organoids and cancer organoids. Normal organoids are derived from normal tissues or cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, cancer organoids are mainly derived from cancer tissues, cancer cells, or genetically engineered pluripotent stem cells [12, 13].

Previous studies have shown that glioblastoma organoids (GBOs) can be established in various ways, such as culturing gene-edited ESCs or iPSCs [14, 15], co-culturing GBM tumor cells with brain organoids [16, 17], and direct cultivation of tumor tissues or tumor cells [18, 19]. However, there is a lack of a comprehensive analysis of the creation method and the applications of GBOs.

Here, we searched the articles on GBOs published in four databases (PubMed, Embase, Web of Science, and Wiley Online Laboratory) in the last three years, compared the generation methods and application areas of various original GBOs, and identified the dominant methods for generating GBOs and the most commonly used GBOs in the study of GBM. This work can provide researchers with a direct and valuable reference for selecting an appropriate method for generating GBOs when studying GSCs and GBM.

Materials and methods

Search strategy

To comprehensively collect the recently published literature on GBOs, we conducted searches in four databases (PubMed, Embase, Web of Science, and Wiley Online Laboratory) from August 2021 to August 2023. We designed the search strategy as follows:

PubMed: (Organoid*[Title/Abstract] AND Glioblastoma*[Title/Abstract])

Embase: (Glioblastoma*:ti,ab AND Organoid*:ab,ti)

Web of Science: (TI = (glioblastoma*) OR AB = (glioblastoma*)) AND (TI = (Organoid*) OR AB = (Organoid*))

Wiley Online Laboratory: (“Organoid*” in Title and “AND Glioblastoma*” in Title) and (“Organoid*” in Abstract and “AND Glioblastoma*” in Abstract)

Inclusion and exclusion criteria

Only English-written literature searched in the four databases was included. However, reviews, conference abstracts, protocols, corrigenda, books, and case studies were excluded. Likewise, articles that did not create human GBOs or lacked detailed information on methods were excluded.

Documents analysis

The materials and methods for creating GBOs in the included literature were focused on and analyzed. Then, the applications of different original GBOs were analyzed.

Results

Search results and articles selection

A total of 295 publications were retrieved from these four databases in the initial search, including 73 publications from PubMed, 133 from Embase, 81 from Web of Science, and eight from Wiley Online Library. After removing duplicates, the predetermined inclusion and exclusion criteria were carried out. Finally, 42 articles were included in the following document analysis (Fig. 1).

Fig. 1 Flow diagram of the article selection process

Most GBOs are derived from one material

Overall, the original materials for generating GBOs in the 42 articles included four types: tumor tissues, tumor cells, iPSCs, and ESCs. A total of 35 articles (83%) used only one type of these materials to generate GBOs, of which 18 articles used GBM cells, 14 used GBM tissues, two used iPSCs, and one used ESCs. Only seven articles (17%) used two types of materials, of which five articles used GBM cells with iPSCs, and two articles used GBM cells with ESCs (Fig. 2). Therefore, GBOs are mainly created using one material.

Fig. 2 Different materials for GBOs in the 42 articles. The numbers in the bracket represent the number (and the percentage) of articles

Direct cultivation is the most common method for creating GBOs

In addition to the different materials, there were also different cultural methods for producing GBOs. The most commonly used method was the direct cultivation of tumor tissues or tumor cells. Of the 42 articles, 32 (76%) used the method to generate GBOs, including 14 directly cultured tumor tissues, 10 cultured primary tumor cells, and eight cultured tumor cell lines such as U87 and U125. The second method was co-culturing tumor cells with normal organoids. Seven (17%, 7/42) articles adopted this method, including co-culturing tumor cells with iPSCs-derived normal organoids (five articles) and with ESCs-derived normal organoids (two articles). The last method was culturing gene-edited multifunctional stem cells, including gene-edited iPSCs (two articles) and gene-edited ESCs (one article) (Fig. 3). Furthermore, we found that in these three articles, tumor protein 53 (TP53), neurofibromin (NF1), and phosphatase and tensin homolog (PTEN) were the edited target genes in iPSCs or ESCs, which were knocked out by CRISPR/Cas9 technology to produce GBOs.

Fig. 3 Different models for creating GBOs in the 42 articles. The numbers represent the number of articles

GBOs produced by Direct Culture of Tumor tissues have the widest applications

Organoids serve as a valuable tool in medicine, pharmacy, life sciences, and other fields. In this review, the applications of GBOs included seven aspects in GBM research, including molecular mechanism (45%, 19/42), therapy (26%, 11/42), cultivation technique (10%, 4/42), drugs (7%, 3/24), microenvironment (5%, 2/42), immunology (5%, 2/42), and cellular characteristics (2%, 2/24). GBOs generated by direct cultivation of tumor tissues had the most applications with all seven aspects, closely followed by GBOs generated by direct cultivation of tumor cells with five aspects and direct cultivation of tumor cell lines with four aspects (Fig. 4).

Fig. 4 Applications of GBOs created by different methods in the 42 articles. The numbers represent the number of articles

Discussion

Accumulating evidence demonstrates that GSCs are the cause of glioblastoma initiation, recurrence, and metastasis. GSCs can give rise to massive, differentially differentiated tumor cells and play an important role in maintaining the architecture and functions of tumor tissues. Therefore, investigating the biological properties of GSCs could shed light on the cure of GBM. Cell culture is an essential technique for stem cell research. However, traditional 2D cell culture has the disadvantage of not mimicking the hierarchical architecture and behavior of in vivo tumor tissues. In order to overcome the shortcomings of 2D cell culture, the organoids technique (3D cell culture) has been established and matured in recent years. Organoids are a novel and promising platform for studying tumorigenesis, anticancer drug screening, and therapy [20, 21]. To investigate the generation methods and the applications of GBOs, we searched a total of 295 publications in PubMed, Embase, Web of Science, and Wiley Online Laboratory databases in the last three years. After screening for the article on human GBOs, 42 articles were included in this review.

Here, we comprehensively analyzed GBOs from three aspects: original materials, generation methods, and applications. Generally, GBOs can be derived from these four types of materials: GBM cells, GBM tumor tissues, gene-edited iPSCs, and gene-edited ESCs. Furthermore, GBOs can be generated by using GBM cells and iPSCs/ESCs together. According to the methods described in the 42 articles, there were three strategies for generating GBOs: (1) direct cultivation of tumor tissues or tumor cells [22–53]; (2) co-cultivation of tumor cells with iPSCs- /ESCs- derived normal organoids [54–60]; and (3) cultivation of gene-edited iPSCs/ESCs [61–63]. Among these methods, direct cultivation of GBM tumor tissues has been used most frequently, followed by direct cultivation of GBM cells and direct cultivation of GBM cell lines such as U87MG and U251. The other two methods were used relatively less frequently, possibly due to the convenience of obtaining GBM tumor tissues and GBM cells and the simplicity of direct culture. Specifically, the first step in the co-cultivation method was to generate normal organoids using iPSCs or ESCs, and then GBM tumor cells were added to these normal organoids. Since iPSCs and ESCs have the ability to self-renew and differentiate, both could serve as a common platform to generate various organoids, including GBOs, colon organoids, and liver organoids. The typical strategy in the gene editing method is to modify some particular genes in iPSCs or ESCs to generate GBOs.

The CRISPR/Cas9 gene editing technique is an ideal tool for gene modification and is widely used to knock out, insert, or mutate target genes [64]. In this review, only three GBOs were created by culturing gene-edited iPSCs or ESCs, among which the CRISPR/Cas9 system was adopted to silence target genes. It indicates that the GRISPR/Cas9 system is an effective tool for creating GBOs. Selecting appropriate target genes is the key to successfully generating GBOs through gene editing. We found that the edited target genes in these three GBOs were the tumor suppressor genes P53, NF1, and PTEN. The TP53 gene encodes a transcription factor, which regulates target gene expression by binding to defined DNA sequences within the genome, influencing cell proliferation, apoptosis, genome stability, and more. Abnormal expression or mutant of P53 is often found in various cancers, such as brain, liver, lung, breast, and bladder cancer cells [65, 66]. The PTEN is an important regulator of cell cycle progression, apoptosis, differentiation, and metastasis and functions as a tumor suppressor by regulating the PI3K/Akt/mTOR signaling pathway [67]. Previous studies have demonstrated that PTEN is related not only to the tumorigenesis and invasion of GBM but also to its progression and therapy response of GBM [68]. Moreover, PTEN is a crucial mediator factor in GBM tumorigenesis regulated by non-coding RNAs, such as miR-1908 and miR-130b [69, 70]. The NF1 gene encodes the neurofibromin protein that is predominantly expressed in the nervous system, whose mutation causes neurofibromatosis type 1 disease. It is an autosomal dominant inherited neurocutaneous disorder and is associated with the development of tumors of the nervous and non-nervous systems, including gliomas. The neurofibromin protein regulates cell biological functions, including proliferation, apoptosis, and migration, by modulating multiple signaling pathways, including Ras/MAPK2 and PI3K/AKT/mTOR [71]. Thus, P53, PTEN, and NF1 are the ideal target genes for generating GBOs, and their simultaneous deletion in iPSCs or ESCs could generate GBOs.

In the 42 articles, GBOs were reported to be used in seven areas of GBM research, including molecular mechanisms, therapy, cultivation technique, drugs, microenvironment, immunology, and cellular characteristics. Further analysis demonstrated that GBOs were mainly used in the studies of molecular mechanisms and therapy of GBM, accounting for 71% of all applications in this study. In detail, GBOs were used to investigate the underlying mechanisms of the occurrence and development of GBM. For example, the mesenchyme homeobox 2 gene increased GBM tumor growth through ERK signaling pathway. The inhabitation of bromodomain and extraterminal domain protein reduced the proliferation and invasion of GBM cells. In the therapy aspect, GBOs could be used to test the effect of new or combination drugs, evaluate new therapy methods, and promote personalized therapies. Regarding cultivation technique, GBOs were applied to establish and optimize GBM cell or tissue culture in vitro. In terms of drugs, GBOs were used in drug screening and studying resistance mechanisms. GBOs displayed the effect of the microenvironment on GSCs or GBM cells. In immunology, GBOs cultured in human plasma-like medium could increase immunologic transcriptional programs of the immune cells in tumor microenvironment. By using GBOs, it was found Aryl hydrocarbon receptor regulated genes linked to intrinsic immunity, proliferation, and migration in GBM [72–74]. Considering the cultivation methods, we found that GBOs created via directly culturing tumor tissues or tumor cells have broader applications than those created via other methods.

Conclusion

GBOs have the obvious advantage of mimicking the hierarchical order and functions of GBM tissues in vivo and are a powerful tool for studying GSCs and GBM. GBOs can be generated by direct culture of tumor tissues, tumor cells, or gene-edited multifunctional stem cells and by co-culture of tumor cells with normal organoids. Simultaneous silencing of P53, NF1, and PTEN by CRISPR/Cas9 could induce iPSCs or ESCs to produce GBOs. GBOs generated by direct culture of GBM tissues have the most applications. This review provides a valuable reference for generating GBOs and their future applications.

Author contributions

P.H. contributed to the conception and design of the work; J.L. and P.H. colected and analyzed the data; P.H. drafted the work and revised it. All authors have read and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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