NFAT Mediates Pro-Tumorigenic Inflammation in Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma
Chuner Guo, Michelle F. Griffin, Annah G. Morgan, Deshka S. Foster, Jennifer B. L. Parker, Michael Januszyk, Hunter G. Lindsay, Nicholas J. Guardino, Rosyli Reveron-Thornton, Peter Y. Xie, Maria Korah, Amanda Gonçalves, Jason L. Guo, Andrea E. Delitto Monica M Dua, Brendan C Visser, George A. Poultsides, Daniel Delitto, Michael T. Longaker, Jeffrey A. Norton
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma, low immunogenicity, and resistance to therapy. Cancer-associated fibroblasts (CAFs) are key stromal cells within the tumor microenvironment (TME) that drive tumor progression. Interleukin-1 (IL-1) promotes fibrosis, pathogenic inflammation, and poor prognosis in PDAC.
Methods: Using publicly available data, we identify the IL-1 signaling axis as one of the key drivers of PDAC inflammation and fibrosis. We then develop a novel mouse model of PDAC, which mimics the inflammatory microenvironment in human PDAC. Using a novel single-cell multiomic approach, we investigate the gene regulatory mechanism underlying the IL-1 signaling axis in human and mouse models of PDAC.
Results: IL1R1+ CAFs activate an inflammatory phenotype associated with elevated NFAT motif activity and gene expression. In vivo, NFAT inhibition in a mouse model of PDAC significantly reduces tumor weight and fibrosis, supporting its pro-tumorigenic role.
Conclusion: Our findings suggest that NFAT mediates IL-1-induced inflammation in PDAC, highlighting its potential as a therapeutic target. This study demonstrates the power of multiomic analyses to uncover therapeutic targets within the complex tumor microenvironment.