靶向突变型p53依赖的胰腺癌中的NPY/NPY1R信号轴会损害转移。
Targeting the NPY/NPY1R signaling axis in mutant p53-dependent pancreatic cancer impairs metastasis.
作者信息
Chambers Cecilia R, Watakul Supitchaya, Schofield Peter, Howell Anna E, Zhu Jessie, Tran Alice M H, Kuepper Nadia, Reed Daniel A, Murphy Kendelle J, Channon Lily M, Pereira Brooke A, Tyma Victoria M, Lee Victoria, Trpceski Michael, Henry Jake, Melenec Pauline, Abdulkhalek Lea, Nobis Max, Metcalf Xanthe L, Ritchie Shona, Cadell Antonia, Stoehr Janett, Magenau Astrid, Chacon-Fajardo Diego, Chitty Jessica L, O'Connell Savannah, Zaratzian Anaiis, Tayao Michael, Da Silva Andrew, Lyons Ruth J, Goldstein Leonard D, Dale Ashleigh, Rookyard Alexander, Connolly Angela, Crossett Ben, Tran Yen T H, Kaltzis Peter, Vennin Claire, Dinevska Marija, Croucher David R, Samra Jaswinder, Mittal Anubhav, Weatheritt Robert J, Philp Andrew, Del Monte-Nieto Gonzalo, Zhang Lei, Enriquez Ronaldo F, Cox Thomas R, Shi Yan-Chuan C, Pinese Mark, Waddell Nicola, Sim Hao-Wen, Chtanova Tatyana, Wang Yingxiao, Joshua Anthony M, Chantrill Lorraine, Evans Thomas R Jeffry, Gill Anthony J, Morton Jennifer P, Pajic Marina, Christ Daniel, Herzog Herbert, Timpson Paul, Herrmann David
机构信息
Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, Sydney, New South Wales, Australia.
School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Kensington, Sydney, New South Wales, Australia.
出版信息
Sci Adv. 2025 Mar 14;11(11):eadq4416. doi: 10.1126/sciadv.adq4416. Epub 2025 Mar 12.
Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present with advanced-stage disease, preventing potentially curative surgery. The neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY and are up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KPC mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout of significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPC migratory capacity on cell-derived matrices. Pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing liver metastasis. Together, our results reveal that NPY/NPY1R signaling is a previously unidentified antimetastatic target in PC.
胰腺癌（PC）是一种具有高度转移性的恶性肿瘤。超过80%的胰腺癌患者就诊时已处于晚期，无法进行可能治愈性的手术。神经肽Y（NPY）系统以其在控制能量稳态中的作用而闻名，也已被证明在一系列癌症类型中促进肿瘤发生，但其在胰腺癌中的作用尚未得到探索。我们发现，在小鼠胰腺癌模型和人类胰腺癌患者中，NPY和[此处原文缺失相关内容]的表达上调。此外，使用基因工程的、自发的KPC胰腺癌小鼠模型，我们证明胰腺特异性和全身敲除[此处原文缺失相关内容]可显著减少向肝脏的转移。我们发现，用NPY1R拮抗剂BIBO3304处理可显著降低KPC在细胞衍生基质上的迁移能力。在脾脏内胰腺癌转移模型中进行药理学NPY1R抑制，重现了我们基因研究的结果，BIBO3304显著减少了肝脏转移。总之，我们的结果表明，NPY/NPY1R信号通路是胰腺癌中一个先前未被识别的抗转移靶点。
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