Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors (GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9low GCP-like tumor cells constitute the bulk of both infant (Math1Cre: Ptch1lox/lox ) and adult ( Ptch1LacZ/+ ) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9 + MATH1 + (GCP), SOX9 + GFAP + (astrocytes) and SOX9 + MATH1 + GFAP + (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre: Sox9lox/lox ) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre: Ptch1lox/lox;Sox9lox/lox ) does not affect tumor formation. Implications: Despite preclinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target. This article is featured in Highlights of This Issue, [p. 1793][1] [1]: /lookup/volpage/19/1793?iss=11

中文翻译：

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SOX9 定义了 SHH 髓母细胞瘤中不同的细胞群，但不是 Math1 驱动的肿瘤形成所必需的

髓母细胞瘤是最常见的恶性儿科脑肿瘤，迫切需要分子靶向和亚组特异性治疗。干细胞因子 SOX9 已被提议作为治疗 Sonic Hedgehog 髓母细胞瘤 (SHH-MB) 亚组肿瘤的潜在治疗靶点，因为它作为 Hedgehog 信号传导的下游靶标以及在功能上促进 SHH-MB 转移和治疗抗性. 然而，SOX9 在髓母细胞瘤发生中的功能需求仍有待确定。在这里，我们报告了以前未记录的 SOX9 表达水平，专门在出生后小鼠小脑的增殖颗粒细胞前体 (GCP) 中，其作为 SHH-MBs 的髓母细胞瘤起始细胞。野生型 GCP 表达的 SOX9 水平低于神经干细胞，成熟的星形胶质细胞和 SOX9low GCP 样肿瘤细胞构成婴儿 (Math1Cre: Ptch1lox/lox) 和成人 (Ptch1LacZ/+) SHH-MB 小鼠模型的主体。人类髓母细胞瘤单细胞 RNA 数据分析揭示了 SHH-MB 中存在三个不同的 SOX9 群体，而在其他髓母细胞瘤亚组中明显不存在：SOX9 + MATH1 + (GCP)、SOX9 + GFAP +（星形胶质细胞）和 SOX9 + MATH1 + GFAP +（潜在肿瘤来源的星形胶质细胞）。为了在功能上解决 SOX9 是否需要作为髓母细胞瘤肿瘤细胞中 Hedgehog 信号传导的下游效应器，我们使用 Math1Cre 模型系统消融了 Sox9。令人惊讶的是，GCP 中 Sox9 的靶向消融（Math1Cre：Sox9lox/lox）显示 SHH-MB 中没有明显的表型和 Sox9 缺失（Math1Cre：Ptch1lox/lox；Sox9lox/lox ) 不影响肿瘤形成。启示：尽管临床前数据表明 SOX9 在 SHH-MB 生物学中起关键作用，但我们的数据反对 SOX9 作为可行的治疗靶点。这篇文章被收录在本期的亮点中，[p. 1793][1][1]：/lookup/volpage/19/1793?iss=11