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

Wenting Du, Natalie Z. Phinney, Huocong Huang, Zhaoning Wang, Jill Westcott, Jason E. Toombs, Yuqing Zhang, Muhammad S. Beg, Thomas M. Wilkie, James B. Lorens, Rolf A. Brekken

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1412-1421
Number of pages10
JournalMolecular Cancer Research
Volume19
Issue number8
DOIs
StatePublished - Aug 1 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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