Spatial heterogeneity of glioblastoma cells reveals sensitivity to NAD+ depletion at tumor edge

摘要: Even after total resection of glioblastoma core lesions by surgery and aggressive post-surgical treatments, life-threatening tumors inevitably recur. A characteristic obstacle in effective treatment is high intratumoral heterogeneity, both longitudinally spatially. Recurrence occurs predominantly at the brain parenchyma-tumor interface, a region termed tumor edge. Given difficulty accessing it surgically, composition edge, harboring cancerous non-cancerous cells, remains largely unknown. Here, to identify phenotypic diversity among heterogeneous edge lesions, we uncovered existence three phenotypically-distinct clonal subpopulations within individual from patients. Clones shared same phenotype, exclusively generating tumor-core cells. In contrast, two distinct subtypes were identified edge: one generated only edge-lesion cells other expanded more broadly establish edge- core-lesions. Using multiple xenograft experimental models mouse brains, development was found require that somatic express NADase CD38, combinedly elevating malignancy. vitro data suggested intracellular activity provoked through intercellular communication between clones normal astrocytes. Systemic tumor-bearing mice with 78c, small-molecule CD38 inhibitor, attenuated formation suggesting its clinical potential pharmacologically eliminate tumor-edge lesions. Collectively, these findings provide novel mechanistic insights into heterogeneity glioblastoma, particularly surgically unresectable, currently understudied