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López Vásquez, C.E.; Gray, C.; Henry, C.; Munro, M.J. Modelling Meningioma Using Organoids. Encyclopedia. Available online: https://encyclopedia.pub/entry/52844 (accessed on 01 July 2024).
López Vásquez CE, Gray C, Henry C, Munro MJ. Modelling Meningioma Using Organoids. Encyclopedia. Available at: https://encyclopedia.pub/entry/52844. Accessed July 01, 2024.
López Vásquez, Clara Elena, Clint Gray, Claire Henry, Matthew J. Munro. "Modelling Meningioma Using Organoids" Encyclopedia, https://encyclopedia.pub/entry/52844 (accessed July 01, 2024).
López Vásquez, C.E., Gray, C., Henry, C., & Munro, M.J. (2023, December 17). Modelling Meningioma Using Organoids. In Encyclopedia. https://encyclopedia.pub/entry/52844
López Vásquez, Clara Elena, et al. "Modelling Meningioma Using Organoids." Encyclopedia. Web. 17 December, 2023.
Modelling Meningioma Using Organoids
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This entry is adapted from the peer-reviewed paper 10.3390/organoids2040017

Meningiomas are the most common tumours of the central nervous system. According to the World Health Organization (WHO), this disease is classified into three different grades: 80% of meningioma patients present with benign grade I tumours, while less than 2% present with malignant grade III meningiomas. Despite affecting thousands of people worldwide, much remains unknown about this disease, and the development of systemic treatments is still far behind in comparison to other types of tumours. Therefore, forming 3D structures (spheroids and organoids) could facilitate research on the mechanisms of formation, proliferation, migration, and invasion of these, for the most part, benign tumours, while also helping in the process of drug development. To date, there are three published methods for the formation of meningioma organoids primarily derived from patient tissue samples. Organoids offer many advantages in the development of treatments because they recapitulate the cellular complexity within tumours. These new methodological advances could open a substantial number of possibilities for the further characterisation and treatment of meningiomas.

meningioma organoids

1. Meningioma

Meningiomas are the most common tumours of the central nervous system [1]. The incidence rate varies from 1.3 to 7.8 cases per 100,000 worldwide [2]. According to the World Health Organization (WHO), this disease is classified into three different grades: grade I is considered a benign tumour, grade II is atypical, and grade III is malignant or anaplastic. Grade I meningiomas are the most common, comprising approximately 80% of all meningiomas diagnosed; ~17% are atypical, and less than 2% are considered malignant [3]. Each meningioma grade is further classified into histological subtypes. Meningothelial is the most common subtype of grade I meningioma (60%), followed by fibrous, transitional, psammomatous, secretory, angiomatous, lymphoplasmacyte-rich, metaplastic, and microcystic subtypes. Grade II meningiomas include three subtypes: atypical, chordoid, and clear cell. Grade III includes papillary, rhabdoid, and anaplastic subtypes [3][4][5].
Meningiomas originate from the meninges [5]. Healthy meninges are composed of different types of cells, such as fibroblasts, which are the majority; arachnoid barrier cells with epithelial characteristics; immune cells; and endothelial cells [6]. The meninges comprise three layers that surround the brain and spinal cord: the dura mater, the arachnoid mater, and the pia mater [7]. These three layers play key roles in the stabilisation and protection of the central nervous system. They also facilitate some immunological responses, including immunosurveillance [8]. One hypothesis establishes that meningiomas originate from precursor cells that are prostaglandin D2 synthase positive (PGDS+). These cells differentiate into arachnoid barrier cells (ABC) and dura border cells (DBC), each of which generates a different meningioma subtype [9][10]. DBC forms fibroblastic meningiomas, whereas ABC originates the meningothelial subtype [9]. Another hypothesis establishes that meningiomas that usually start forming in the arachnoid layer originate from arachnoidal cap cells [10][11]. These arachnoid cap cells, which are involved in the reabsorption of cerebrospinal fluid, have high metabolic activity and different junctions between them which are key to developing their function. Desmosomes and hemidesmosomes allow cells to adhere tightly to one another, whereas cadherin junctions facilitate their flexibility. This layer of the meninges is not well-vascularised; therefore, the cells also require gap junctions that allow the transport of different nutrients and metabolites between cells [12][13].
According to the tumour grade and subtype, meningiomas contain cells with different characteristics. Most cells possess mesenchymal features, such as intracellular aggregates of collagen and sometimes metaplastic changes, similar to cartilage and bone tissue. However, most meningioma tumour cells are identified as meningothelial-like cells, indicating that they are derived from the meningeal layers. These cells create a spherical structure that tends to mineralise to produce whorl formations and psammoma bodies [3][14]. Other properties of these tumours include bleached chromatin and cytoplasmic inclusions in the cell nuclei [3]. Since meningiomas can possess a wide array of molecular characteristics, their grades and subtypes are typically classified according to their histological appearance [10].
The difference in grading resides in the histology of the tumours. Grade I meningioma subtypes are characterised by cellular features. For example, the meningothelial subtype contains syncytial/meningothelial-like cells that have round nuclei and form whorls, the fibrous subtype contains cells with a spindle morphology, and the angiomatous subtype has a significant vascular component comprising endothelial cells. Grade II meningiomas typically present with an increase in mitotic cells, are more invasive (going further than the pial layer), have smaller cells, spontaneous necrosis, and an uninterrupted pattern with less growth or a larger nucleus. Grade III tumours present with a higher number of mitotic cells and show characteristics like melanoma, sarcoma, and carcinoma [15][16].
In grade I meningiomas, the meningothelial subtype presents as medium-sized cells with a high number of nuclei, and some with cytoplasmic inclusions. Cell limits are difficult to identify, and some groups of cells are surrounded by fibrous septa. The fibrous subtype is characterised by elongated spindle cells organised in parallel and surrounded by a matrix primarily composed of collagen [16][17]. Psammomatous meningiomas are identified by an abundance of psammoma bodies. This subtype is often observed in patients with spinal tumours. In contrast, the transitional subtype shows a combination of the previous subtypes described above. Some cells have psammoma bodies, some have spindled cells, and some are epithelioid [16].
As the name indicates, angiomatous lesions are identified by many blood vessels within the tumour. Cells often show a foamy-like cytoplasm and nuclear atypia. This group usually presents in combination with the microcystic subtype, which displays features like those of the arachnoid layer, where the cells are elongated with spaces between them [16].
Metaplastic meningioma is similar in appearance to classical meningioma histology, but sometimes acquires features of other tissues such as cartilage, bone, and connective tissue. The secretory subtype displays epithelial characteristics and gland-like structures filled with eosinophilic secretions. This is the only subtype that does not possess mutations in NF2, but they are characterised by abundant KLF4 and TRAF7 mutations. The lymphoplasmacyte-rich subtype is identified by inflammation, presenting with infiltrating immune cells such as macrophages, lymphocytes, and plasma cells [13][16][17].
Grade II meningiomas are divided into three subtypes. Chordoid tumours present with elongated cells, eosinophilic cytoplasm and a matrix with basophilic characteristics [16]. The clear cell subtype is characterised by abundant glycogen in the cytoplasm [18]. Among other criteria, atypical tumours, which include all grade II tumours, are prone to brain invasion and have a mitotic index close to 4.
Grade III meningiomas include papillary tumours that possess papillary structures, a high proliferation rate, and necrosis with prolongation of the blood vessels; the rhabdoid subtype characterised by eosinophilic cytoplasm with cytoplasmic inclusions, whorl formations, and a mitotic index ≥4; and the anaplastic subtype, which has a mitotic index of ≥20, occasional meningothelial whorls and psammoma bodies, and features resembling melanoma, sarcoma, or carcinoma [16][17].
Most meningiomas harbour somatic mutations in NF2, SMO, AKT1, KLF4, POLR2A, and/or TRAF7 and germline mutations in SUFU, with certain mutations associated with each tumour subtype and location [11][19][20]. Neurofibromin 2 (NF2) is a gene involved in the formation of the merlin protein that connects proteins from the membrane and cytoskeleton and is also considered a tumour suppressor gene. Mutations in this gene or deletions in the chromosome where it resides (22q) are the most common molecular characteristics for identifying meningiomas [10][21][22][23][24][25]. Smoothened (SMO) and suppressor of fused homolog (SUFU) participate in the Hedgehog signalling pathway implicated in the proliferation, growth, and migration of cells [19][20][26][27]. ATK1 is a proto-oncogene that encodes a serine-threonine kinase that plays a key role in the PI3K pathway implicated in growth signalling [27][28][29]. Krüppel-like factor 4 (KLF4) is involved in cell proliferation, growth, and differentiation [27][30]. RNA polymerase II subunit A (POLR2A) is commonly mutated in meningothelial meningiomas [31][32][33]. This somatic mutation is also associated with meningioma development in the tuberculum sellae [32]. TNF receptor-activated factor 7 (TRAF7), which is mutated in >20% of meningiomas, encodes an E3 ubiquitin ligase that oversees the degradation of other proteins [27][34].

2. Organoids to Model Meningioma

Cerebral organoids were first established in 2013 [35][36], but it was not until eight years later that the first meningioma organoids were described in the literature.
Yamazaki et al. [37] developed a protocol to form organoids starting from a meningioma commercial cell line (IOMM-Lee), as well as from patient-derived cells, of which 66.66% were primary tumours and 33.34% were recurrent. Tissue samples were digested using collagenase IV and mechanical dissociation, and red blood cell lysis was performed using ACK Lysing Buffer (ThermoFisher Scientific, Waltham, MA, USA). Single cells were suspended in Neurobasal Medium supplemented with N-2 and B-27 (all ThermoFisher), 50 ng/mL FGF (fibroblast growth factor), and 50 ng/mL EGF (epidermal growth factor; both R&D Systems, Minneapolis, MN, USA), and then seeded in Matrigel (Corning, Corning, NY, USA) in a six-well plate. The medium was refreshed every few days to allow the cells to divide slowly and form organoids inside the matrix [37]. The similarity of the organoids to their parental tumour was investigated via IHC using antibodies against the meningioma diagnostic markers SSTR2A and Ki-67 and via whole-exome sequencing and structural variant analysis to confirm the conservation of NF2 mutations and chromosome 22q deletions. The organoids formed from grades II and III showed a higher expression of Ki-67, associated with proliferation and STAT6, specifically in the cytoplasm of the meningioma cells. Furthermore, FOXM1 has been identified as a contributor to meningioma progression by increasing proliferation, which was confirmed by RNA interference using two FOXM1-specific siRNAs [37]. This is the first published report of patient-derived meningioma organoids that successfully recapitulated the molecular and histological features of parental tissues from each patient, though the authors did not specify the cell types found in the meningioma organoids. A limitation in the process of meningioma organoid formation has been recognised—the need for organoids to be surrounded by normal tissue and to study the interactions between these cells to understand the behaviour, invasiveness, and proliferation of meningioma tumours [37].
The second method, by Chan et al. [38], utilised single cells obtained from the mechanical and enzymatic digestion of tissue samples collected from patients with meningioma. Two digestion methods were tested, one using 70 ng/mL collagenase IV and 124 ng/mL dispase, and the other using 0.05% trypsin, with the trypsin method leading to greater cell viability (89.8%) than the collagenase/dispase (86.5%). Once the cell suspension was obtained, the cells were strained through a 70 µM filter before being resuspended in Matrigel and dispensed cautiously into a culture dish in the form of 30 µL droplets. After the Matrigel had solidified, fresh media containing DMEM, 10% foetal bovine serum (FBS), 1% penicillin/streptomycin (antibiotics), 1× B-27, 1× N-2, 1% HEPES buffer, 1% glutamine, 20 ng/mL EGF, and 20 ng/mL FGF were added. Organoid morphology was studied under a microscope at 1, 7, and 14 days, and a progression from single ovaloid and spindle cells to meningioma cell aggregates with cell-to-cell interactions was observed. The authors reported distinct cell niches within the organoids but did not specify the cell types present in each [38]. To check whether the organoids recapitulated the characteristics of the parental meningioma tumours, haematoxylin and eosin (H&E) staining and immunostaining for epithelial membrane antigen (EMA/MUC1) were performed. All results demonstrated that the meningioma organoids obtained were similar to meningioma tissues, showing ovaloid and spindle cells, as seen in the parental tumours. In addition, the cells formed denser aggregates in the peripheral region of the extracellular matrix. With all the experiments conducted, the researchers demonstrated that during the organoid culture process, meningioma cell morphology changed over time [38].
The third protocol was published in early 2023 by Huang et al. [39]. Before establishing an organoid model, meningioma samples were studied using scRNA-seq, revealing eight distinct clusters of cells within the meningioma tumours, with most of them being part of the immune system: malignant cells, dendritic cells, macrophages, monocytes, neutrophils, NK cells, T cells, and tumour-infiltrating B lymphocytes. M2-like polarised macrophages were predominant in higher grades [39]. They then established a meningioma organoid protocol which differs from others by starting from small pieces of patient-derived tissue rather than a single-cell digest, allowing the retention of most cell types and their native cell–cell interactions. The tissues were minced carefully to achieve a size of ~1 mm3, washed with DPBS, treated with red blood cell lysis buffer, and then 20–30 pieces of tissue were transferred to an ultra-low attachment six-well plate (Corning) and grown in suspension. The plate was kept on a shaker in an incubator, and the organoid medium was changed every three days. The organoid medium contained DMEM, 10% FBS, 1% Pen/Strep, 1× GlutaMax, 1× non-essential amino acids (all ThermoFisher), and 0.25 µL/mL insulin (Sigma-Aldrich, St. Louis, MO, USA). H&E staining and immunostaining against SSTR2A (meningioma cells), CD31 (blood vessels), CD68, and CD3 (immune cells) were performed, as well as an extensive study utilising whole-exome sequencing and scRNA-seq to investigate the cellular heterogeneity within organoids. All these studies demonstrated that meningioma organoids recapitulated the gene expression, mutations, histological features, and cell populations (tumour cells, endothelial cells, tumour-infiltrating macrophages, and T lymphocytes) of the parental tumours [39]. They also identified a SULT1E1+ subpopulation within parental tumours, which was implicated in the progression of meningiomas to a higher grade. This subpopulation was also identified in meningioma organoids. SULT1E1+ cells were confirmed to be invasive by using a murine orthotopic xenograft model. The authors completed their study by exploring possible targeted treatments for this cell population [39].
All three organoid-forming protocols were established mostly from female meningioma samples, reflecting the higher incidence in females. Huang et al. [39] reported successful organoid formation from 12 grade I meningiomas and 4 grade II meningiomas within a week from a total of 21 tumour samples (subtypes: meningothelial, angiomatous, fibrous, microcystic, and atypical). The brain regions of tumour development were not mentioned [39].
Similarly, Yamazaki et al. [37] formed organoids from 11 grade I meningiomas (meningothelial and secretory subtypes), 3 grade II meningiomas (atypical) and 1 grade III meningioma (anaplastic) within a week, with a 100% success rate [37]. The organoids were passaged at least ten times, yielding successful results [37]. Tumour locations were reported: four were from the falx, with others being from the convexity, middle cranial fossa, cavernous sinus, tuberculum sellae, parasagittal, olfactory groove, and petroclival (skull base) areas [37].
Finally, Chan et al. [38] established organoids from five of eight patient samples: four from grade I and one from grade II, all derived from different locations (two frontal lobe, two spheroid ridge, two convexity, one parietal lobe, one occipital lobe). The authors did not specify meningioma subtypes [38].
The largest difference between the protocols was the starting material. While Yamazaki et al. [37] and Chan et al. [38] digested the tissue completely to obtain single cells that were embedded in Matrigel, Huang et al. [39] used larger tissue pieces (1 mm3) which were suspended in media.
Current meningioma organoid formation protocols have limitations. Firstly, the variability in the media formulations reported to date could affect the reproducibility of organoid derivation and subsequent experiments. In some cases, the density of Matrigel used could also determine the success rate of organoid formation. The use of bioreactors seems to be uncommon but could help maintain meningioma organoids for longer periods of time. In researchers' experience, foetal bovine serum (FBS) is necessary for the growth of grade I meningioma cells. Although it is an animal-derived product that may interfere with some organoid applications, FBS aids cell proliferation, viability, and growth [40]. Therefore, standardised protocols are needed for the reproducible formation of meningioma organoids, and scientists establishing new protocols should provide more detailed steps to allow for greater reproducibility and consistency.
Even though all meningioma organoids described above recapitulated the cell morphology and staining seen in the parental tumours, researchers think there should be more studies to further characterise the cell types present in meningioma tumours and to identify the stem cells present in the organoids, employing flow cytometry, transcriptomics, proteomics, and/or metabolomics. The cellular composition of the healthy meninges has been well studied, revealing the presence of arachnoid cells, fibroblasts, endothelial cells, and immune cell populations; however, a similar study in meningioma tumours is lacking. Another outstanding question in the development of meningioma organoids is to establish the period of time in which these organoids can be kept alive.

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Clara Elena López Vásquez
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Clint Gray
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Claire Henry
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Matthew J. Munro
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