TY - JOUR
T1 - AXL is a key factor for cell plasticity and promotes metastasis in Pancreatic cancer
AU - Du, Wenting
AU - Phinney, Natalie Z.
AU - Huang, Huocong
AU - Wang, Zhaoning
AU - Westcott, Jill
AU - Toombs, Jason E.
AU - Zhang, Yuqing
AU - Beg, Muhammad S.
AU - Wilkie, Thomas M.
AU - Lorens, James B.
AU - Brekken, Rolf A.
N1 - Funding Information:
We thank Drs. Gray Pearson and Srinivas Malladi and members of the Brekken lab for helpful discussion, and Dave Primm for editorial assistance. The work was supported by NIH grants R01 CA192381 and U54 CA210181 Project 2 and the Effie Marie Cain Scholarship in Angiogenesis Research (to R.A. Brekken).
Publisher Copyright:
©2021 American Association for Cancer Research
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-20-0860
DO - 10.1158/1541-7786.MCR-20-0860
M3 - Article
C2 - 33811159
AN - SCOPUS:85112802335
VL - 19
SP - 1412
EP - 1421
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 8
ER -