Wilm’s Tumor 1-Expressing Stromal Cells Promote Pancreatic Cancer Progression

Abstract Cancer-associated fibroblasts (CAFs) 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 Wilm’s 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 cancer. Here, 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, where they give 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. While this population might constitute a potential therapeutic target, caution will be needed to avoid exacerbating immune suppression.