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 - 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
SN - 1541-7786
VL - 19
SP - 1412
EP - 1421
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -