Cell reports · 2026
NFAT mediates pro-tumorigenic inflammation in cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.
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Guo Chuner, Griffin Michelle F, Morgan Annah G, Foster Deshka S, Parker Jennifer B L, Januszyk Michael, Lindsay Hunter G, Guardino Nicholas J, Reveron-Thornton Rosyli, Xie Peter Y, Valencia Caleb, Kuhnert Maxwell M, Korah Maria, Gonçalves Amanda, Guo Jason L, Delitto Andrea E, Agolia James P, Tabora Angela D, Dua Monica M, Visser Brendan C, Poultsides George A, Delitto Daniel, Longaker Michael T, Norton Jeffrey A
Аннотация
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 single-cell multi-omic 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 multi-omic analyses to uncover therapeutic targets within the complex TME.