1. AXL Is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer
- Author
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Rolf A. Brekken, Wenting Du, Jason E. Toombs, Jill M. Westcott, Zhaoning Wang, James B. Lorens, Thomas M. Wilkie, Yuqing Zhang, Natalie Z. Phinney, Huocong Huang, and Muhammad Shaalan Beg
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Epithelial-Mesenchymal Transition ,education ,Cell Plasticity ,Deoxycytidine ,Receptor tyrosine kinase ,Article ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Pancreatic cancer ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,Tumor Microenvironment ,Medicine ,Animals ,Humans ,Neoplasm Metastasis ,Molecular Biology ,biology ,business.industry ,Receptor Protein-Tyrosine Kinases ,MERTK ,medicine.disease ,Phenotype ,Gemcitabine ,Axl Receptor Tyrosine Kinase ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,business ,medicine.drug ,TYRO3 ,Carcinoma, Pancreatic Ductal - 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.
- Published
- 2020