Abstract
Abstract Oligodendroglioma evolution is incompletely understood. Here we analyze serial oligodendroglioma samples to define genomic and cellular mechanisms underlying treatment resistance. RNA sequencing was performed on 53,406 spatial transcriptomes from 31 oligodendrogliomas (IDH mutant, 1p/19q-codeleted) that were resected from 16 patients. There were 15 CNS WHO grade 2 and 16 grade 3 oligodendrogliomas, which were stratified for temporal progression across grades (n=5 grade 2 to 2, n=5 grade 2 to 3, n=6 grade 3 to 3) and treatments between serial resections (n=2 TMZ/RT, n=2 TMZ, n=1 mTOR inhibition, n=1 IDH inhibition, n=10 surgical monotherapy). Spatial transcriptomic clusters were defined using cell signature gene sets, cell cycle analysis, differentially expressed marker genes, immunohistochemistry, spatial copy number alterations (CNAs), and deconvolution of 18,628 oligodendroglioma single-cell transcriptomes from 16 independent patients. Specificity was tested using immunofluorescence on independent oligodendrogliomas that did not recur after surgical monotherapy (n=8 samples, median follow-up 8.4 years) and spatial transcriptomic sequencing on 8 matched-paired astrocytomas from 4 patients. Integrated uniform manifold approximation and projection revealed a proneural/NPC-like cluster that was enriched in grade 3 oligodendroglioma samples and represented the starting point in oligodendroglioma lineage differentiation using RNA velocity, Monocle, and subclonal spatiotemporal CNA evolution. Comparison across treatment regimens showed (1) enrichment of the proneural/NPC-like cluster in recurrent versus primary tumors that were treated with surgical monotherapy, (2) enrichment of a proneural/OPC-like cluster and depletion of an oligodendrocyte-like cluster after TMZ/RT, (3) enrichment of proneural/NPC-like and immediate-early response clusters after TMZ/RT, (4) enrichment of the oligodendrocyte-like cluster following mTOR inhibition, and (5) enrichment of cancer associated fibroblasts (CAFs) following IDH inhibition. These data show the spatiotemporal landscape of oligodendroglioma is associated with branched lineage differentiation that is modified by postoperative therapy, and suggest that therapy-dependent druggable dependencies may exist to treat oligodendrogliomas that are resistant to standard interventions.
Published Version
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