Abstract We profiled N = 22 cases of sonic hedgehog (SHH) medulloblastoma (MB) from UCSF and CBTN via single-nucleus RNA sequencing (snRNA-seq). We sequenced n = 17 treatment naïve diagnostic and n = 5 recurrent specimens, including 4 longitudinal pairs. Select cohorts were profiled via single-cell assay for transposase-accessible chromatin (scATAC-seq; N = 13) and spatial transcriptomics (N = 6). Whole-genome sequencing data for N = 10 longitudinal SHH MB specimens from CBTN were integrated into the analysis. Overall tumor mutational burden increased at recurrence. However, metrics of selection pressure for recurrent-specific alterations indicated neutral evolution. While the composition of primary and recurrent tumors was similar, there were significant differences observed in cellular phenotypes and paracrine signaling. We identified a progenitor-like population that upregulated VEGFA and PI3K pathways genes at recurrence. These cells expressed markers of endoplasmic reticulum stress but were not confined to regions of hypoxia. Rather, these cells resided in niches of sprouting angiogenesis that were characterized by elevated angiopoietin, apelin, and VEGFA signaling, as well as increased infiltration by myeloid cells. The VEGFA signature we identified was prognostic in CBTN data and correlated with P53 mutation status. We performed genetic lineage tracing through recurrence via phylogenetic inference on mutation calls in single cells. Our ongoing efforts to map the evolution of treatment-resistant clones will be presented. Taken together these studies shed light on the cellular evolution of SHH MB under therapy.
Jain et al. (Fri,) studied this question.
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