胰腺导管腺癌 (PDAC) 是一种越来越多的癌症，它导致 90% 的患者死亡，其中大多数患者接受姑息化疗。我们鉴定出神经元五聚蛋白 1 (NPTX1) 是一种癌症分泌蛋白，在转移过程中在人类和小鼠 PDAC 细胞中过度表达，并鉴定出以 Ig 样结构域 2 (AMIGO2) 作为其受体的粘附分子。分子、遗传、生化和药理学实验表明，分泌的 NPTX1 细胞自主地作用于 AMIGO2 受体，驱动 PDAC 转移定植于肝脏（PDAC 转移的主要部位）。 NPTX1-AMIGO2 信号传导增强缺氧生长，并且是缺氧诱导因子 1a (HIF1a) 核保留和功能所必需的。 NPTX1 在人类 PDAC 肿瘤中过度表达，并在肝转移中上调。使用高亲和力单克隆抗体靶向 NPTX1 进行治疗可显着减少 PDAC 肝转移定植。因此，我们将 NPTX1-AMIGO2 确定为 PDAC 中 HIF1a 缺氧反应的可药物化关键上游调节因子。

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer secreted protein that becomes over-expressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia induced factor-1a (HIF1a) nuclear retention and function. NPTX1 is over-expressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1a hypoxic response in PDAC.