TMIC-74. A patient-derived orthotopic meningioma model for interrogation of the tumor microenvironment

Abstract Meningiomas represent the most prevalent primary intracranial tumors, with the majority classified as WHO grade 1, typically benign tumors exhibiting slow growth. In contrast, WHO grade 2 and 3 meningiomas display increased histopathological aggressiveness, characterized by increased growth, recurrence rates, invasiveness and poorer prognoses. Emerging evidence suggests that tumor microenvironment (TME) plays a critical role in tumor aggressiveness; however, its contribution to meningioma pathobiology is poorly understood. This study aims to establish a patient derived orthotopic xenograft (PDOX) meningioma model to elucidate the role of the TME in driving tumor aggressiveness and to identify novel therapeutic targets. To this end, primary tumor cells derived from meningiomas of various WHO grades were isolated and grown as monolayer cultures, spheroids, and organoids. Additionally, the immortalized meningioma WHO Grade 3 IOMM-Lee cell line was used to represent high-grade tumors. To investigate tumor formation and TME, these cells were implanted intracranially into NMRI nude mice. Tumor development was confirmed via MRI. Subsequently, whole brains were collected either 6-9 months post-inoculation or upon symptom onset, followed by sectioning and analysis through immunohistochemistry. Moreover, tissue samples are being collected for spatial transcriptomics to further investigate molecular profiles. Preliminary analysis of brains implanted with IOMM-Lee cells revealed a 100% tumor take rate, with high Ki67 expression, indicative of significant proliferation. A notable presence of microglia and macrophages (IBA1, CD204) was observed, suggesting involvement of the TME. Current efforts focus on expanding the cohort by including more patients with different grades of meningiomas. This model will provide valuable insights into the cellular composition, heterogeneity, and tumor-immune cell interactions. Ultimately, it will uncover potential therapeutic targets for meningioma and enable their functional validation. This project is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 945322 (LEAD) and Lundbeck Foundation.