STEM-18. GENETIC LINEAGE TRACING OF MEDULLOBLASTOMA UNDER THERAPY WITH SPATIAL CONTEXT

Le résumé fourni par la source

Abstract Recent single-cell studies implicate the glutamatergic lineage of the rhombic lip (RL) as the origin of group (G) 3/4 medulloblastomas (MBs) and a stalled differentiation program as underlying their malignant transformation. It is unknown, however, if G3/4 MBs exhibit cellular plasticity as has been observed in glioma. The effect of therapy on cellular hierarchies in G3/4 MBs is unknown. We profiled N=57 G3/4 MB frozen specimens obtained from the University of California, San Francisco Brain Tumor Center and the Children’s Brain Tumor Network biobanks via single-nucleus RNA and epigenetic sequencing. This cohort included 43 diagnostic and 14 patient-matched recurrent specimens. We profiled N=32 FFPE specimens via Xenium single-cell spatial transcriptomics. We performed genetic lineage tracing in intracranial implants of G3 MB cell lines derived from primary and metastatic disease using engineered barcodes, and in clinical specimens using endogenous mutations. Remarkably, xenografts from primary tumors produced similar cell types, in similar proportions to those found in treatment-naive human MBs. Moreover, the distribution of cell types found in xenografts was conserved at the level of individual clones, indicating cell-intrinsic regulation of tumor composition. Single-cell phylogenetic analysis demonstrated significant rates of dedifferentiation events from unipolar brush-like cells to RL-progenitor phenotypes. This plasticity was increased in recurrent specimens and in metastatic models compared to models and samples derived from primary disease. Samples with higher plasticity exhibited greater spatial heterogeneity, while samples with lower rates of dedifferentiation had more structured spatial organization. These studies show that G3/4 MB cellular composition is homeostatic in treatment-naive disease and conserved at the level of individual clones. Yet, these tumors exhibit plasticity that is exacerbated by therapy and affects spatial organization.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.