METB-08. Unraveling the cellular diversity and spatial architecture of infant-type hemispheric gliomas using multi-omic profiling
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.006 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".