Speaker
Description
Medulloblastomas are malignant cerebellar tumors that represent approximately 20% of all pediatric brain tumors. Molecular profiling categorizes these tumors into four subgroups: WNT, SHH, Group 3 (G3), and Group 4 (G4). G3 and G4 tumors account for more than 65% of pediatric cases and exhibit the highest rates of metastasis, relapse, and mortality. Current models predominantly reflect G3 tumors, inadequately capturing the biological complexity and diversity of G3 and G4 medulloblastomas. These tumors likely originate from excitatory progenitors of the rhombic lip, a structure with developmental differences between mice and humans, potentially explaining the limited efficacy of murine models. To develop accurate human-specific models of medulloblastoma tumorigenesis, we differentiated iPSCs into cerebellar organoids and validated their cerebellar identity and cellular diversity. Remarkably, G3 and G4 medulloblastoma tumors predominantly affect boys over girls, indicating a potential role of sex hormones in tumor initiation. Supporting this, recent findings by Kelava et al. (2022) demonstrated that male sex steroids (androgens) enhance the proliferation of excitatory neurogenic progenitors in cerebral organoids. Consequently, increased proliferation of rhombic lip progenitors in males could elevate their susceptibility to oncogenic events and malignant transformation. To investigate this hypothesis, we engineered male and female iPSC lines with an mNeonGreen reporter downstream of transcription factors specific to G3 (LMX1A) and G4 (EOMES) progenitor populations. Differentiation of these lines into cerebellar organoids followed by androgen treatment significantly increased the proportion of LMX1A+ and EOMES+ progenitors, confirming androgen-driven expansion of these rhombic lip progenitors. Currently, we are evaluating the tumorigenic potential of these progenitors through lineage-specific, conditional activation of oncogene combinations identified in G3/G4 medulloblastoma patients. These novel organoid models offer valuable tools for investigating human-specific mechanisms of G3/G4 medulloblastoma initiation, facilitating therapeutic discovery and improving outcomes for pediatric patients.
| Author(s) | Luca Bianchini*, Frederik Arnskötter*, Patricia Benites, Lena M. Kutscher |
|---|---|
| Affiliation(s) | "Developmental Origins of Pediatric Cancer and Hopp Children’s Cancer Center (KiTZ) and German Cancer Research Center (DKFZ)/Heidelberg/Germany, Faculty of Biosciences and Ruprecht Karl University of Heidelberg/Heidelberg/Germany, Developmental Origins of Pediatric Cancer and Hopp Children’s Cancer Center (KiTZ) and German Cancer Research Center (DKFZ)/Heidelberg/Germany, Developmental Origins of Pediatric Cancer and Hopp Children’s Cancer Center (KiTZ) and German Cancer Research Center (DKFZ)/Heidelberg/Germany, Developmental Origins of Pediatric Cancer and Hopp Children’s Cancer Center (KiTZ) and German Cancer Research Center (DKFZ)/Heidelberg/Germany," |
