Cancer-associated fibroblasts drive early pancreatic cancer cell invasion via the SOX4/MMP11 signalling axis.

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. [Display omitted] • myCAFs enhances metastatic capacity of PDAC cells via secreting various regulators. • The reprogramming from iCAFs to myCAFs is associated with poor prognosis. • SOX4 is aberrantly activated in myCAFs and promotes secretion of MMP11. • SOX4+ myCAFs is a potential therapeutic target of metastatic PDAC. [ABSTRACT FROM AUTHOR]