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

Author:

Yamashita Daisuke,Botta Davide,Cho Hee Jin,Guo Xiaoxian,Ozaki Saya,Flanary Victoria L,Sirota Inna,Gao Mu,Yamaguchi Shinobu,Nakano Mayu A,Zhou Fen,Zhou Hongyi,Kondo Toru,Kunieda Takeharu,Crossman David K,Kornblum Harley I,Gorospe Myriam,Nam Do-Hyun,Zamboni Nicola,Skolnick Jeffrey,Gu Zhenglong,Lund Frances E,Nakano Ichiro

Abstract

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

Publisher

Cold Spring Harbor Laboratory

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