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静止期人胶质母细胞瘤癌症干细胞在化疗后驱动肿瘤起始、扩增和复发。

Quiescent human glioblastoma cancer stem cells drive tumor initiation, expansion, and recurrence following chemotherapy.

机构信息

Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

Brain Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

出版信息

Dev Cell. 2022 Jan 10;57(1):32-46.e8. doi: 10.1016/j.devcel.2021.12.007.

DOI:10.1016/j.devcel.2021.12.007
PMID:35016005
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8820651/
Abstract

We test the hypothesis that glioblastoma harbors quiescent cancer stem cells that evade anti-proliferative therapies. Functional characterization of spontaneous glioblastomas from genetically engineered mice reveals essential quiescent stem-like cells that can be directly isolated from tumors. A derived quiescent cancer-stem-cell-specific gene expression signature is enriched in pre-formed patient GBM xenograft single-cell clusters that lack proliferative gene expression. A refined human 118-gene signature is preserved in quiescent single-cell populations from primary and recurrent human glioblastomas. The F3 cell-surface receptor mRNA, expressed in the conserved signature, identifies quiescent tumor cells by antibody immunohistochemistry. F3-antibody-sorted glioblastoma cells exhibit stem cell gene expression, enhance self-renewal in culture, drive tumor initiation and serial transplantation, and reconstitute tumor heterogeneity. Upon chemotherapy, the spared cancer stem cell pool becomes activated and accelerates transition to proliferation. These results help explain conventional treatment failure and lay a conceptual framework for alternative therapies.

摘要

我们检验了这样一个假说，即神经胶质瘤中存在静止的癌症干细胞，它们能够逃避抗增殖疗法。对基因工程小鼠的自发性神经胶质瘤进行功能特征分析揭示了具有重要静止特性的干细胞样细胞，这些细胞可直接从肿瘤中分离出来。衍生的静止性癌症干细胞特异性基因表达特征在缺乏增殖基因表达的预先形成的患者 GBM 异种移植单细胞簇中富集。在原发性和复发性人神经胶质瘤的静止单细胞群体中保留了经过改进的 118 个人类基因的特征。在保守特征中表达的 F3 细胞表面受体 mRNA 通过抗体免疫组化鉴定静止肿瘤细胞。F3 抗体分选的神经胶质瘤细胞表现出干细胞基因表达，增强在培养中的自我更新能力，驱动肿瘤起始和连续移植，并重建肿瘤异质性。在化疗后，被保留的癌症干细胞池被激活，并加速向增殖的转变。这些结果有助于解释常规治疗失败，并为替代疗法奠定了概念框架。

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