Abstract Infant-type hemispheric gliomas (IHGs) are rare receptor tyrosine kinase (RTK)-driven tumors with fusions in ALK, ROS1, MET, and NTRK genes. Aberrant RTK activation may interfere with normal neural development, derailing developing cells onto hyperproliferative and divergent trajectories. Key questions about tumor composition, cell of origin, and RTK fusion’s role in tumor formation remain unanswered. We analyzed a cohort of RTK-fused gliomas (n = 13 IHGs) using single-cell multi-omic RNA/ATAC-seq (n = 20) or SmartSeq2 (n = 7) and generated an atlas of over 90’000 transcriptomes and 1M spatially resolved cells. Integration with brain development datasets identified five progenitor-like cancer populations spanning a continuum of states: Radial glia-like, NPC/Neuronal-like, OPC-like, GPC/Astrocyte-like, and cycling. Trajectory analysis revealed a gradient of cancer cells expressing both developmental and mature brain lineage genes. RNA velocity pinpointed Radial glia-like cells as the likely origin, diverging into GPC/Astrocyte-like, NPC/Neuronal-like, and OPC-like lineages. RTK fusion-positive cells were identified across all cells, highlighting early progenitors as drivers of tumorigenesis. Interestingly, a higher proportion NPC/Neuronal-like cells was found in IHGs, suggesting an earlier oncogenic hit in those patients, and lacked MES-like tumor cells found in other gliomas. Chromatin analysis revealed dynamic accessibility changes and transcription factor motifs across cell populations. Radial-glia-like cells displayed open chromatin linked to undifferentiated cells, resembling the state of other cancers. Moreover, GPC/Astrocyte-like and NPC/Neuronal-like populations showed neurogenesis and synaptic function. Motif analysis identified lineage-defining factors and oncogenic regulators, illustrating the role of chromatin remodeling in plasticity and lineage specification. Finally, we mapped the spatial architecture using MERFISH in n = 4 IHGs and uncovered a heterogeneous spatial distribution of cell states. While lacking global structure, cancer cells exhibited higher spatial coherence and clustered into localized regions, suggesting tumor organization recapitulates aberrant brain morphogenesis. Taken together, our multi-omics atlas describes the cellular and spatial heterogeneity of IHGs, providing new insights into their developmental origins, unique biology, and clinical implications.
Micheli et al. (Fri,) studied this question.
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