Abstract
Cancer-associated fibroblasts (CAF) are a prevalent cell population in the microenvironment of pancreatic cancer. The pancreas harbors diverse resident cell populations that can differentiate into CAFs, and the cell of origin might contribute to CAF heterogeneity. Expression of the transcription factor Wilms tumor 1 (WT1) marks mesothelial cells as well as a transcriptionally distinct population of fibroblasts in the normal pancreas. WT1 expression also identifies a population of CAFs in both human and mouse pancreatic cancers. In this study, we investigated the contribution of WT1+ mesenchymal cells to CAF populations and evaluated the functional role of WT1+ stromal cells in pancreatic cancer. Lineage tracing revealed that WT1+ cells expand in pancreatic cancer, giving rise to a population of inflammatory CAFs. Depletion of WT1+ stromal cells reduced orthotopic tumor growth, with increased immunosuppressive macrophage activation and reduced infiltration of CD8+ and FOXP3+ T cells. Notably, the reduction in tumor weight observed with WT1+ cell depletion was independent of CD8+ and CD4+ T cells. WT1+ CAFs expressed high levels of tumor-promoting ligands that likely interact directly with the tumor epithelium to drive tumor progression. Accordingly, WT1-expressing cell-depleted tumors had reduced epithelial MAPK activation. Together, these data show that WT1+ stromal cells represent a tumor-promoting CAF population. Although this population might constitute a potential therapeutic target, caution will be needed to avoid exacerbating immune suppression. SIGNIFICANCE: WT1-expressing mesenchymal cells in the normal pancreas can give rise to inflammatory cancer-associated fibroblasts in pancreatic cancer that promote cancer growth independent of T-cell responses, expanding understanding of cancer-associated fibroblast origins.