NFAT Mediates Pro-Tumorigenic Inflammation in Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma [human multiome]

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: Human PDAC specimens were obtained from patients undergoing surgery at Stanford Hospital under a Stanford University approved IRB protocol (#45051). The patients were counseled in the pre-operative area by one of the manuscript authors. The aims of the study were discussed with the patient. Participation was entirely voluntary. Written, informed consent was obtained from all the patients included in this study prior to surgery. Tissue specimens were collected by one of the authors from the pathologist once the PDAC tumor specimen had been inked (from a non-critical part of the tumor), placed directly into sterile saline, and kept on ice for transport. Tumor specimens were dissociated into single nuclei and profiled for gene expression and chromatin accessibility simultaneously from the same nucleus.