Identification of genes regulated by NFAT5-SMADs complex
Oncogenic KRAS is now considered a druggable target; however, multiple mechanisms contribute to the development of resistance to KRAS-targeted therapy. A significant factor in therapy resistance is the alteration in cell state or cellular plasticity, exemplified by the epithelial-to-mesenchymal transition (EMT) phenotype. In pancreatic ductal adenocarcinoma (PDAC), the negative correlation between addiction to oncogenic KRAS signaling and EMT has been observed, yet the role of cell plasticity and its underlying mechanisms in governing resistance remain unclear. Our findings reveal that the pivotal EMT driver, TGFß, facilitates KRAS bypass in PDAC through the nuclear factor NFAT5. NFAT5 interacts with canonical TGFß factors SMAD3 and SMAD4, inducing EMT and therapy resistance. To unravel the regulatory role of the NFAT5-SMADs complex in KRAS* bypass, we conducted transcriptomic analysis in TGFß-treated, KRAS*-depleted iKPC spheroids. Overall design: To investigate the cooperative function of NFAT5-SMADs complex in the regulation of KRAS* bypass, we knocked down or inhibited NFAT5 and SMAD3 in mouse PDAC cells.