Abstract
Abstract INTRODUCTION Exploring tumor-neuronal interactions is essential for comprehending brain tumor proliferation, chemotherapy resistance, and patient survival. While glioma research has made significant strides, our understanding of tumor-neuronal interactions in pediatric brain tumors, notably Embryonal Tumors with Multilayered Rosettes (ETMRs), remains limited. METHODS To elucidate tumor-neuronal interactions in ETMRs, we developed a 3D model by co-aggregating the human ETMR cell line BT-183 with human induced pluripotent stem cells (iPSCs) and allowing them to mature into forebrain organoids for 30 days, forming ETMR-forebrain organoids (ETMR-FBO). We further employed single-cell RNA sequencing to compare the gene expression profile of healthy forebrain organoids (FBO) with the ETMR-FBOs. Additionally, we conducted immunohistochemistry of 3D model sections for comparative evaluation and spatial transcriptomics of murine and human primary ETMR samples. RESULTS Our integrated dataset of 48,764 cells of healthy FBOs (n = 4) and ETMR-FBOs (n = 6) revealed that ETMR tumor cells impeded the neuronal differentiation of the FBO cells. The ETMR-FBOs exhibited a significant enrichment of neuro-stem cells (67% vs 49%), accompanied by a reduction of more differentiated neuronal cells. Comparative trajectory analysis confirmed a blockage of neuronal maturation/differentiation in ETMR-FBOs compared to controls without ETMR cells. Immunohistochemistry further confirmed an enrichment of SOX2-positive/synaptophysin-negative neuronal progenitors in the organoid areas closest to the tumor border. Additionally, we identified upregulated extracellular matrix-related pathways, particularly integrin and YAP/TEAD signaling, in the neuro-stem cell compartment of ETMR-FBOs. This implies a tumor-specific mechano-signaling mechanism influencing the neuronal differentiation state of the tumor microenvironment. CONCLUSION Our findings suggest that mechano-signaling-related tumor-neuronal interactions in ETMR contribute to the formation of an immature neuronal niche. Targeting mechano-signaling may hold promise for innovative therapies by disrupting tumor architecture and enhancing susceptibility to chemotherapy.
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