Li Si, Li Wei, Miao Yuqi, Gao Meixi, Jia Yanfei, Chen Zhenhua, Chen Xi, Pan Taotao, Zhang Shuangfeng, Xing Zhifang, Han Shuping, Sun Xue-Lian, Wei Xiaochan, Liu Zhiming, Zhou Wentao, Wu Wentao, Liu Fangzheng, Han Lei, Zhu Hongmei, Ye Hongying, Liu Longqi, Li Yinqing, Zhang Peng, Gong Jian, Tian Yongji, Ai Youwei, Cao Peng, Wu Di, Qi Xiangbing, Gui Songbai, Wu Qing-Feng
State Key Laboratory of Molecular Development Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100101, China.
Sci Transl Med. 2024 Dec 18;16(778):eadn6763. doi: 10.1126/scitranslmed.adn6763.
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 ()-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.
发生在下丘脑 - 垂体轴沿线的肿瘤会接收来自神经内分泌神经元的轴突投射，但神经内分泌神经元活动是否驱动肿瘤生长仍不清楚。颅咽管瘤是一种常见的鞍上肿瘤，倾向于侵犯下丘脑，导致严重的内分泌和代谢紊乱。在此，我们开发了两种自发动物模型，忠实地再现了乳头型颅咽管瘤的分子病理学、临床表现和转录组谱。通过高通量药物筛选，我们鉴定出74种具有强大抗肿瘤功效的化合物。给予（）-苯磺酸氨氯地平可在体内实现肿瘤消退，可能是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，对神经内分泌神经元活动进行化学遗传学操纵双向调节肿瘤细胞生长，这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，并为有效化疗的临床探索提供了有希望的途径。
