Central nervous system neuroblastoma with FOXR2 activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2 specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 originate from LHX6+/DLX+ interneuron lineages, a lineage-of-origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics.

中文翻译：

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FOXR2 靶向 LHX6+/DLX+ 神经谱系驱动 CNS 神经母细胞瘤


具有 FOXR2 激活的中枢神经系统神经母细胞瘤 （NB-FOXR2） 是一种脑半球的高级别肿瘤，是一种新发现的分子实体。肿瘤表达双神经元和神经胶质标志物，导致频繁的误诊，并且关于 FOXR2 在其发生中的作用的信息有限。为了确定它们的细胞起源，我们在大块和单细胞水平上分析了 NB-FOXR2 肿瘤的转录组，并将这些图谱与正常大脑的大型单细胞参考相结合。NB-FOXR2 肿瘤定位于源自内侧神经节隆起（腹侧端脑的祖细胞结构域）的 LHX6+/DLX+ 谱系。体内产前 Foxr2 靶向小鼠诱导的产后皮质肿瘤神经节隆起，概括了人类 NB-FOXR2 特异性分子特征。在小鼠模型中分析 FOXR2 与染色质的结合分析揭示了与 ETS 转录网络的关联，以及 FOXR2 在协调胶质生成起始的关键转录因子上的直接结合。这些数据表明，NB-FOXR2 起源于 LHX6+/DLX+ 中间神经元谱系，该谱系不同于其他 FOXR2 驱动的脑肿瘤，突出了腹侧端脑来源的中间神经元对 FOXR2 驱动的肿瘤发生的易感性，并表明 FOXR2 诱导的神经胶质细胞程序激活可能解释了这些肿瘤中的混合神经元和少突胶质细胞特征。更广泛地说，这项工作强调了大脑发育的系统分析，作为一种为体内建模定位致癌靶向的有效方法，这对于罕见肿瘤的研究和治疗方法的开发至关重要。