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

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor, predominantly triggered by the acquisition of mutant KRAS, and is present in approximately 95% of PDAC cases. The recent introduction of KRAS inhibitors has been a source of tremendous enthusiasm; however, therapeutic resistance has emerged, and combination approaches are needed. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6, a dual-specificity phosphatase that modulates ERK1/2 phosphorylation and RAS pathway activity, has emerged as an important regulator of KRAS-MAPK signaling. Analysis across diverse bulk RNA-seq datasets revealed that DUSP6 is markedly overexpressed in primary tumor samples compared to non-tumoral pancreatic tissue. Interestingly, both human bulk and single-cell RNA-seq data indicated that DUSP6 was upregulated in epithelial cells within the tumor. Further examination showed that DUSP6 was also overexpressed in metastatic samples relative to primary tumor samples, and this upregulation correlated with the quasi-mesenchymal/squamous molecular subtype. Pertaining to its clinical significance, patients with high DUSP6 expression exhibited a poorer prognosis for overall survival than those with low expression. Subsequent gene set enrichment analysis of publicly available datasets revealed the enrichment of pathways associated with cell migration and metabolism in metastatic samples. To elucidate the role of DUSP6 in these pathways, we developed PDAC cell lines stably knocked down DUSP6 and observed a concurrent increase in ERK/MAPK activation. Additionally, suppression of DUSP6 demonstrated PDAC cell-specific alterations in migratory capacity . Next, we assessed the metabolism of PDAC cell lines following DUSP6 knockdown and observed a notable increase in basal glycolysis. Interestingly, despite the observed alterations in migratory capacity and glycolytic metabolism upon DUSP6 modulation, the combined approach of DUSP6 downregulation and glycolysis inhibition failed to affect the observed migratory phenotype, suggesting that glycolytic demands did not drive the migratory phenotype . In summary, these findings suggest that DUSP6 elicits two independent functions in PDAC: migratory capacity and glycolysis metabolism, providing new insights into the function of DUSP6 in PDAC.