DUSP6 is upregulated in metastasis and influences migration and metabolism in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with KRAS mutations in ~ 95% of cases. While KRAS inhibitors have shown promise, therapeutic resistance necessitates combination approaches. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6 has emerged as an important dual-specificity phosphatase regulating KRAS-MAPK signaling. DUSP6 is markedly overexpressed in PDAC tumors compared to normal pancreatic tissue, with transcriptomic and single-cell RNA-seq analyses revealing its enrichment in epithelial tumor cells, especially in metastatic lesions. High DUSP6 expression correlates with the quasi-mesenchymal/squamous molecular subtype and poorer survival outcomes. Gene set enrichment analyses linked DUSP6 to pathways involved in cell migration and metabolism in metastatic samples. Functionally, DUSP6 knockdown in PDAC cells increases ERK/MAPK activation and alters migration. Metabolic profiling revealed enhanced basal glycolysis upon DUSP6 suppression. However, combined glycolysis inhibition and DUSP6 knockdown did not affect migration, suggesting that glycolytic changes are not the driver of altered migratory behavior. These findings reveal that DUSP6 independently regulates migration and metabolism in PDAC, emphasizing its dual role in disease progression. This study underscores the significance of DUSP6 as a potential therapeutic target and provides new insights into its contributions to PDAC progression.