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

Mol Cancer Res. 2021 Aug;19(8):1412-1421. doi: 10.1158/1541-7786.MCR-20-0860. Epub 2021 Apr 2.

Abstract

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 AXL 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. IMPLICATIONS: These studies implicate AXL as a marker of undifferentiated PDA cells and a target for therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axl Receptor Tyrosine Kinase
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Plasticity / drug effects
  • Cell Plasticity / physiology*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / physiology
  • Female
  • Gemcitabine
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / pathology*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / physiology

Substances

  • Biomarkers, Tumor
  • Proto-Oncogene Proteins
  • Deoxycytidine
  • Receptor Protein-Tyrosine Kinases
  • Gemcitabine
  • Axl Receptor Tyrosine Kinase