Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.

胰腺癌的特点是大量的结缔组织增生，这是一种由细胞外和细胞成分组成的致密基质，其中癌症相关成纤维细胞（CAF）是主要的细胞成分。然而，CAF 的起源组织仍然存在争议。在这里，我们通过对小鼠进行全面的谱系追踪研究来确定胰腺 CAF 的组织起源。我们发现内脏间充质（胰腺上皮起源于内胚层周围的胎儿细胞层）产生了正常胰腺中的大多数常驻成纤维细胞。在胰腺癌遗传小鼠模型中，常驻成纤维细胞扩增并构成 CAF 的大部分。单细胞 RNA 分析可识别胎儿内脏间充质、成体成纤维细胞和 CAF 共有的基因表达特征，表明持久的转录程序是内脏谱系分化的基础。总之，这项研究定义了胰腺间充质成分的系统发育，并提供了对胰腺形态发生和肿瘤发生的见解。