Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma

Abstract

Background & aims: Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous 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 populations 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⁺ fibroblasts 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.

Keywords: Cancer-Associated Fibroblasts (CAFs); Gli1; Heterogeneity; Lineage-Trace; Pancreas.