eEF2K is a poor prognostic factor and novel molecular target in pancreatic cancer: regulating tumor growth and progression via the tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with an average survival time of only six months following diagnosis, even with currently available therapies. Thus, PDAC represents a significant therapeutic challenge, necessitating a deeper understanding of its biology and tumor microenvironment (TME) to develop more effective treatments and improve patient outcomes. Here, we report that the expression of Eukaryotic Elongation Factor-2 Kinase (eEF2K) is associated with shorter patient survival and demonstrate that eEF2K signaling is critical for the PDAC tumor growth and regulated by the TME. Furthermore, in vivo targeted genetic inhibition of eEF2K suppressed tumor growth in two different PDAC mouse models, reduced tumor-associated macrophages (TAMs), and induced marked apoptosis in tumor tissues without any signs of toxicity. Our data suggest that eEF2K knockdown diminishes the activity of the AXL receptor tyrosine kinase and reduces the expression of macrophage-derived factors, such as Monocyte Chemoattractant Protein-1 (MCP1), along with the Gas6/AXL signaling pathway in PDAC cells. Additionally, analysis of the NCI-TCGA PDAC patient database further showed that eEF2K expression, in the presence of TAM markers, correlates with even shorter patient survival. TAM-released factors, such as MCP1, Gas6, and exosomes, induce eEF2K expression in PDAC cells, as well as the activity of AXL, SRC, VEGF, Snail, and MMP2, contributing to epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and angiogenesis. In conclusion, our findings reveal for the first time that eEF2K is a critical oncogenic driver of PDAC tumor growth and thus targeting eEF2K represents a promising and novel therapeutic strategy for PDAC.