Wilms Tumor 1-Expressing Stromal Cells Promote Pancreatic Cancer Progression

Date:	January 16, 2026
PMID:	PMC12809115
Category:	N/A
Authors:	Allison C Bischoff, Kristee Brown, Emily L Lasse Opsahl, Hannah R Watkoske, Carlos E Espinoza, Jude Ogechukwu Okoye, Alberto C Olivei, Leah M Green, Ridesh Rai, Stephanie The, Wei Yan, Aaron D denDekker, Eileen S Carpenter, Jiaqi Shi, Filip Bednar, Timothy L Frankel, Yaqing Zhang, Marina Pasca di Magliano
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.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center