NFAT Mediates Pro-Tumorigenic Inflammation in Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma [mouse VIVIT]
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. Using a novel single-cell multiomic approach, we investigate the IL-1 signaling axis in human and mouse models of PDAC, identifying nuclear factor of activated T cells (NFAT) transcription factors as key mediators. 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. 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. Overall design: To test the effects of NFAT inhibition in vivo, we used the orthotopic allograft KPC PDAC model described previously. KPC cells were injected into the suture-ligated pancreas, followed by a 2-week interval to ensure tumor induction. Mice were then treated with intratumoral injections of saline or VIVIT, a small peptide inhibitor of NFAT. Tissues were harvested and analyzed 2 weeks following intratumoral injection