Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Acta Neuropathol. 2012 Apr;123(4):587-600. doi: 10.1007/s00401-012-0968-6. Epub 2012 Mar 11.
Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis. Indeed, such Shh-mediated metabolic reprogramming fuels tumor progression, in an E2F1- and FASN-dependent manner. Here, we show that the nutrient sensor PPARγ is a key component of the Shh metabolic network, particularly its regulation of glycolysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposed medulloblastoma cells-of-origin, Shh stimulation elicits a marked induction of PPARγ alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPARγ expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPARγ and/or Rb inactivation inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcriptional regulator define a novel mechanism through which Shh signaling engages the nutrient sensing machinery in brain cancer, controls the cell cycle, and regulates the glycolytic index. This also reveals a dominant role of Shh in the etiology of glucose metabolism in medulloblastoma and underscores the function of the Shh → E2F1 → PPARγ axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These findings emphasize the value of PPARγ downstream of Shh as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors.
Sonic hedgehog（Shh）信号通路在发育过程中至关重要，其异常在人类恶性肿瘤谱中很常见。在小脑，Shh 信号通路的过度活跃与毁灭性的小儿脑肿瘤髓母细胞瘤有关。我们之前证明，新生脂质合成的过度表达是 Shh 驱动的髓母细胞瘤的标志， hedgehog 信号通路使 Rb/E2F 肿瘤抑制复合物失活，以促进脂肪生成。事实上，这种 Shh 介导的代谢重编程以 E2F1 和 FASN 依赖的方式推动肿瘤进展。在这里，我们表明营养传感器 PPARγ 是 Shh 代谢网络的关键组成部分，特别是其对糖酵解的调节。我们的数据表明，在原代小脑颗粒神经前体细胞（CGNPs）中，即拟议的髓母细胞瘤细胞起源，Shh 刺激伴随着主要糖酵解标志物一起引起 PPARγ 的显著诱导。这在发育中小脑活跃增殖的 Shh 反应性 CGNPs 中也有记录，并且 PPARγ 表达在体内 Shh 驱动的髓母细胞瘤中显著升高。重要的是，PPARγ 的药理学阻断和/或 Rb 失活抑制 CGNP 增殖，驱动髓母细胞瘤细胞死亡，并延长体内携带髓母细胞瘤动物的存活时间。这种有丝分裂的 Shh 信号与主要营养传感器和代谢转录调节剂的耦合，定义了 Shh 信号在脑癌中参与营养感应机制、控制细胞周期以及调节糖酵解指数的新机制。这也揭示了 Shh 在髓母细胞瘤葡萄糖代谢病因学中的主导作用，并强调了 Shh→E2F1→PPARγ 轴在改变脑癌中底物利用模式以有利于肿瘤生长中的作用。这些发现强调了 Shh 下游的 PPARγ 作为 hedgehog 依赖性和/或 Rb 失活肿瘤的全局治疗靶点的价值。
