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.

中文翻译：

---

一种可靶向的分泌神经蛋白驱动胰腺癌转移定植和 HIF1a 核滞留


胰腺导管腺癌 （PDAC） 是一种越来越多地被诊断出的癌症，导致 90% 的患病患者死亡，其中大多数患者接受姑息性化疗。我们确定神经元五聚素 1 （NPTX1） 是一种癌症分泌蛋白，在转移进展过程中在人和小鼠 PDAC 细胞中过表达，并确定了以 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 在细胞中自主作用于 AMIGO2 受体，以驱动肝脏的 PDAC 转移定植——PDAC 转移的主要部位。NPTX1-AMIGO2 信号转导增强了缺氧生长，并且是缺氧诱导的因子-1a （HIF1a） 核保留和功能的关键需求。NPTX1 在人 PDAC 肿瘤中过表达，在肝转移中上调。用高亲和力单克隆抗体靶向 NPTX1 的治疗性靶向显着减少了 PDAC 肝转移定植。因此，我们将 NPTX1-AMIGO2 确定为 PDAC 中 HIF1a 低氧反应的可成药关键上游调节因子。