Journal
MOLECULAR CANCER RESEARCH
Volume 19, Issue 8, Pages 1412-1421Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-20-0860
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Funding
- NIH [R01 CA192381, U54 CA210181]
- Effie Marie Cain Scholarship in Angiogenesis Research
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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.
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.
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