AXL Is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the United States, has a high metastatic rate, and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, is a driver of metastasis and immune suppression in multiple cancer types. Here we use single-cell RNA-sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXI, expression correlates with classic markers of epithelial-to-mesenchymal transition. We demonstrate that AXL deficiency extends survival, reduces primary and metastatic burden, and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, we demonstrate that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA.

Automated summary

The study found that AXL is highly expressed in PDA tumor cells and correlates with markers of epithelial-to-mesenchymal transition. AXL deficiency extended survival, reduced primary and metastatic burden, and enhanced sensitivity to gemcitabine in mice. AXL-positive poorly differentiated tumor cells were crucial for PDA progression and metastasis, highlighting the potential of AXL as a therapeutic target.