Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma

BACKGROUND & AIMS: Although the healthy pancreas con-sists mostly of epithelial cells, pancreatic cancer and the pre-cursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroin-flammatory stroma that includes a substantial and heteroge-neous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast pop-ulations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis. METHODS: We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1(+) or Hoxb6+ fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis. RESULTS: Although in the healthy pancreas Gli1(+) fibroblasts and Hoxb6(+) fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1(+) fibro-blasts expand dramatically, whereas Hoxb6(+) cells do not. CONCLUSIONS: Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1(+) and Hoxb6(+) fibroblasts and found only Gli1(+) expanded to contribute to the stroma during pancreatic carcinogenesis.