Tumors occurring along the hypothalamus-pituitary axis receive axonal projection from neuroendocrine neurons, but it remains unclear whether neuroendocrine neuronal activity drives tumor expansion. Craniopharyngioma is a common suprasellar tumor with a propensity for invading the hypothalamus, leading to devastating endocrine and metabolic disorders. Here, we developed two autochthonous animal models that faithfully recapitulate the molecular pathology, clinical manifestations, and transcriptomic profiles of papillary craniopharyngioma. Using high-throughput drug screening, we identified 74 compounds with potent antitumor efficacy. The administration of ( S )-amlodipine besylate achieved tumor regression in vivo, potentially by abrogating calcium transients and neuron-to-tumor chemical transmission. Chemogenetic manipulation of neuroendocrine neuronal activity bidirectionally regulated tumor cell growth in our mouse model, suggesting that craniopharyngioma hijacks hypothalamic neurons to promote tumor progression. These findings deepen our understanding of suprasellar tumor biology and offer promising avenues for clinical exploration of effective chemotherapies.

中文翻译：

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用于药物筛选的颅咽管瘤建模揭示了肿瘤生长的神经元机制


沿下丘脑-垂体轴发生的肿瘤接受来自神经内分泌神经元的轴突投射，但目前尚不清楚神经内分泌神经元活动是否驱动肿瘤扩张。颅咽管瘤是一种常见的鞍上肿瘤，易侵入下丘脑，导致毁灭性的内分泌和代谢紊乱。在这里，我们开发了两个本土动物模型，它们忠实地概括了状颅咽管瘤的分子病理学、临床表现和转录组学特征。使用高通量药物筛选，我们确定了 74 种具有有效抗肿瘤功效的化合物。（ S ）-苯磺酸氨氯地平的施用可能在体内实现了肿瘤消退，可能通过消除钙瞬变和神经元到肿瘤的化学传递。在我们的小鼠模型中，神经内分泌神经元活动的化学遗传学操作双向调节肿瘤细胞生长，表明颅咽管瘤劫持下丘脑神经元以促进肿瘤进展。这些发现加深了我们对鞍上肿瘤生物学的理解，并为临床探索有效的化疗提供了有希望的途径。