Novel Human Meningioma Organoids Recapitulate the Aggressiveness of the Initiating Cell Subpopulations Identified by ScRNA‐Seq

Abstract

High-grade meningioma has an unsatisfactory outcome despite surgery and postoperative radiotherapy; however, the factors driving its malignancy and recurrence remain largely unknown, which limits the development of systemic treatments. Single-cell RNA sequencing (scRNA-Seq) technology is a powerful tool for studying intratumoral cellular heterogeneity and revealing the roles of various cell types in oncogenesis. In this study, scRNA-Seq is used to identify a unique initiating cell subpopulation (SULT1E1 + ) in high-grade meningiomas. This subpopulation modulates the polarization of M2-type macrophages and promotes meningioma progression and recurrence. A novel patient-derived meningioma organoid (MO) model is established to characterize this unique subpopulation. The resulting MOs fully retain the aggressiveness of SULT1E1 + and exhibit invasiveness in the brain after orthotopic transplantation. By targeting SULT1E1 + in MOs, the synthetic compound SRT1720 is identified as a potential agent for systemic treatment and radiation sensitization. These findings shed light on the mechanism underlying the malignancy of high-grade meningiomas and provide a novel therapeutic target for refractory high-grade meningioma.

Modelling Meningioma Using Organoids: A Review of Methodologies and Applications

“…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 [68]. They also identified a SULT1E1 + subpopulation within parental tumours, which was implicated in the progression of meningiomas to a higher grade.…”

“…Spheroids can be cultivated with or without growth factors, whereas organoids must be cultured with specific factors [60]. However, spheroids can be formed within 24 h, whereas organoids take longer to form, ranging from weeks to months [55,60,68,69].…”

“…The third protocol was published in early 2023 by Huang et al [68]. 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.…”

“…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 [68]. 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.…”

Zebrafish—A Suitable Model for Rapid Translation of Effective Therapies for Pediatric Cancers

“…Transcriptional analysis of GBM organoids revealed possible ligand-receptor interactions between tumor and organoid cells [22]. Huang et al developed an organoid model for meningioma, and immunohistochemistry analysis revealed striking similarities in cellular heterogeneity between meningioma patient samples and meningioma organoids, which include tumor cells, T-lymphocytes, macrophages, and vascular endothelial cells [23]. However, high-cost, complex model development protocols, lack of proper vasculature, and poor controllability limit the applications and clinical implications of these models [24].…”