胰导管腺癌（PDAC）以丰富的癌相关成纤维细胞（CAFs）、早期周围神经侵犯（PNI）和微血管侵犯（MVI）为特征。然而，PDAC早期侵袭过程中的CAFs分化轨迹和潜在的分子机制尚未完全阐明。本研究中，我们整合并重新分析了国家地球科学数据中心（NGDC）数据库中的单细胞数据，并证实了肌成纤维细胞样CAF（myCAFs）介导上皮间质转化（EMT），通过分泌血管生成和转移调控因子增强PDAC细胞的侵袭能力。此外，我们构建了CAF分化轨迹，并揭示了从iCAFs向myCAFs的重编程与不良预后的关联。在机制上，SOX4在myCAFs中异常激活，促进了MMP11的分泌，最终诱导了早期癌细胞侵袭。综上所述，我们的结果全面展示了早期侵袭PDAC患者的转录组学概述，并揭示了myCAFs与癌细胞之间的细胞间相互作用，为早期侵袭PDAC的治疗提供了潜在的靶点。 版权所有©2023 Elsevier B.V. 发布。

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant cancer-associated fibroblasts (CAFs), early perineural invasion (PNI) and microvascular invasion (MVI). However, the differentiation trajectories and underlying molecular mechanisms of CAFs in PDAC early invasion have not been fully elucidated. In this study, we integrated and reanalysed single-cell data from the National Geoscience Data Centre (NGDC) database and confirmed that myofibroblast-like CAFs (myCAFs) mediated epithelial-mesenchymal transformation (EMT) and enhanced the invasion abilities of PDAC cells by secreting regulators of angiogenesis and metastasis. Furthermore, we constructed a differentiation trajectory of CAFs and revealed that reprogramming from iCAFs to myCAFs was associated with poor prognosis. Mechanistically, SOX4 was aberrantly activated in myCAFs, which promoted the secretion of MMP11 and eventually induced early cancer cell invasion. Together, our results provide a comprehensive transcriptomic overview of PDAC patients with early invasion and reveal the intercellular crosstalk between myCAFs and cancer cells, which suggests potential targets for early invasion PDAC therapy.Copyright © 2023. Published by Elsevier B.V.