Netrin-1 前馈机制通过肝星状细胞激活、类视黄醇和 ELF3 信号传导促进胰腺癌肝转移。
Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling.
发表日期：2023 Nov 02
作者：
Crissy Dudgeon, Anthony Casabianca, Chris Harris, Charline Ogier, Mélanie Bellina, Stephany Fiore, Agnes Bernet, Benjamin Ducarouoge, David Goldschneider, Xiaoyang Su, Jason Pitarresi, Aram Hezel, Subhajyoti De, Wade Narrow, Fady Soliman, Cory Shields, Debora Barbosa Vendramini-Costa, Orjola Prela, Lan Wang, Igor Astsaturov, Patrick Mehlen, Darren R Carpizo
来源：
Cell Death & Disease
摘要：
转移性胰腺导管腺癌 (PDAC) 的生物学特性与原发性肿瘤不同，因为细胞可塑性的变化受不同转录组的控制。需要针对这种独特生物学的治疗策略。我们检测到 PDAC 肝转移中神经元轴突引导分子 Netrin-1 的上调，通过其依赖受体 (DR)、uncoorded-5b (Unc5b) 发出信号，以促进体外和体内转移。 Netrin-1 诱导机制涉及一个前馈循环，其中 PDAC 分泌的细胞外囊泡表面的 Netrin-1 通过诱导肝星状细胞活化和视黄酸分泌来准备转移生态位，进而通过以下途径上调播散性肿瘤细胞中的 Netrin-1： RAR/RXR 和 Elf3 信令。虽然这种机制促进 PDAC 肝转移，但它也确定了治疗的脆弱性，因为可以使用抗 Netrin-1 疗法来靶向使用 Unc5b DR 细胞死亡机制来抑制转移。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.