Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secreted proteins and prevent ER stress. We found that pancreatic ductal adenocarcinomas (PDACs) overexpress the myelin regulatory factor (MYRF), an ER membrane-associated transcription factor (TF) released by self-cleavage. MYRF was expressed in the well-differentiated secretory cancer cells, but not in the poorly differentiated quasi-mesenchymal cells that coexist in the same tumor. MYRF expression was controlled by the epithelial identity TF HNF1B, and it acted to fine-tune the expression of genes encoding highly glycosylated, cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed signs of ER stress, impaired proliferation, and an inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypocellular tumors. These data indicate a role of MYRF in the control of ER homeostasis in highly secretory PDAC cells.

内胚层起源的许多肿瘤由高度分泌的癌细胞组成，这些癌细胞必须适应内质网（ER）的活性才能使分泌的蛋白质正确折叠并防止ER应激。我们发现胰腺导管腺癌（PDAC）过表达髓磷脂调节因子（MYRF），通过自我切割释放的ER膜相关转录因子（TF）。MYRF在分化高的分泌癌细胞中表达，但在分化低的准癌细胞中不表达共生于同一个肿瘤中的间充质细胞。MYRF的表达受上皮同一性TF HNF1B的控制，它的作用是微调编码高度糖基化，富含半胱氨酸的分泌蛋白的基因的表达，从而防止ER超负荷。缺乏MYRF的PDAC细胞在体外表现出ER应激，增殖受损和无法形成球体的迹象，而在体内则产生高度分泌但增殖不良和细胞不足的肿瘤。这些数据表明MYRF在高度分泌的PDAC细胞中ER稳态控制中的作用。