Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with a dismal prognosis due to distant metastasis. Through an analysis of large RNA sequencing and proteomics datasets, we found that high KRT7 expression in PDAC patients was correlated with liver metastasis and poor survival. A functional investigation revealed that the overexpression of KRT7 promoted liver metastasis but did not affect tumor cell proliferation in vivo or in vitro. Analysis of scRNA-Seq data from 24 PDAC samples revealed a negative correlation between KRT7 expression in PDAC cells and cancer-associated fibroblast (CAF) infiltration, and this was further confirmed in orthotopic tumor model mice injected with KRT7-overexpressing PDAC cells, which led the development of to a prometastatic niche with reduced ECM deposition. Mechanistically, KRT7 in PDAC cells promoted the secretion of FGF2, which inhibited CAF proliferation and ECM-related gene transcription through the Wnt/β-catenin pathway. Moreover, targeting FGF2 decreased liver metastasis in vivo. Our study revealed that KRT7 promotes PDAC liver metastasis by remodeling the extracellular matrix niche through FGF2-fibroblast crosstalk and provides a promising strategy for preventing PDAC liver metastasis.