Overexpression of Nuclear Factor of Activated T-cells (NFAT) Transcription Factors Drives Chemoresistance and Poor Outcomes in Pancreatic Cancer.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with high recurrence and poor survival (5-year survival rate: approximately 10%) despite curative resection. Identifying molecular drivers of PDAC recurrence remains a significant challenge. PDAC is characterized by dense stromal hyperplasia that may influence tumor cell-specific gene expression. We aimed to identify genes associated with early recurrence using patient-derived xenograft (PDX) models, focusing on the calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway. Gene expression profiles were analyzed in PDX models derived from PDAC tumors. Differential gene expression (DEG) analysis was conducted to identify pathways linked to early recurrence. Immunohistochemical (IHC) analysis of 165 resected PDAC specimens was performed to evaluate NFAT protein expression. Multivariate Cox regression identified independent prognostic factors for recurrence and survival. Chemoresistance was examined by silencing NFAT1 and NFAT5 in PDAC cell lines and measuring changes in the half-maximal inhibitory concentration (IC₅₀) of chemotherapeutic agents. DEG analysis revealed enrichment of the calcineurin-NFAT signaling cascade. Higher expression of NFAT1 and NFAT5 were significantly associated with early recurrence. IHC revealed NFAT1 expression in 53 (32.1%) samples, NFAT5 in 104 (63.0%), and coexpression in 43 (26.1%). Multivariate analysis identified lymphatic invasion, incomplete resection, and NFAT1/NFAT5 coexpression as independent predictors of poor prognosis. Dual knockdown of NFAT1 and NFAT5 significantly reduced the IC₅₀ of multiple chemotherapeutic agents. Coexpression of NFAT1 and NFAT5 is associated with early recurrence, poor survival, and chemoresistance in PDAC. Targeting the NFAT signaling pathway may improve treatment outcomes in PDAC.