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Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Victoria H. Cruz, … , Alberto E. Bremauntz, Rolf A. Brekken
Victoria H. Cruz, … , Alberto E. Bremauntz, Rolf A. Brekken
Published April 2, 2019
Citation Information: JCI Insight. 2019;4(9):e126117. https://doi.org/10.1172/jci.insight.126117.
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Research Article Oncology

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB–dependent manner. These findings demonstrate that TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl/TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.

Authors

Victoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, Rolf A. Brekken

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Figure 5

Loss of Tbk1 reduces lung colonization.

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Loss of Tbk1 reduces lung colonization.
(A) Representative images of lun...
(A) Representative images of lungs from NOD/SCID mice sacrificed 12 days after i.v. injection with Tbk1+/+ or Tbk1Δ/ΔKIC tumor cells (100,000 cells injected per mouse, n = 7 mice/group). (B) H&E sections of lungs from A, highlighting the tumor nodules. Original magnification, ×4 and ×20 (insets). (C) Number of tumor nodules from A. (D) Lung weights from A. Results are representative of mean ±SEM. ***P < 0.001; ****P < 0.0001 by unpaired, 2-tailed t test.

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