AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

Abstract

<jats:title>Abstract</jats:title><jats:p>Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the US, 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, has been identified as 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 AXL expression correlates with classic markers of mesenchymal tumor cells. We demonstrate that <jats:italic>AXL-deficiency</jats:italic> extends survival, reduces primary and metastatic burden and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in <jats:italic>AXL-deficient</jats:italic> mice displayed a more differentiated histology, higher nucleoside transporter expression and a more active immune microenvironment compared to PDA in <jats:italic>wild-type</jats:italic> mice. Finally, we demonstrate that AXL-positive mesenchymal tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target for PDA patients.</jats:p>