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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 1

TBK1 is highly expressed in pancreatic cancer.

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TBK1 is highly expressed in pancreatic cancer.
(A) Total and p-TBK1 (S17...
(A) Total and p-TBK1 (S172) expression in wild-type KRAS (wt) or mutant active KRAS (mut) HPNE or PDA cell lines. Tbk1Δ/Δ mouse embryonic fibroblasts served as a negative control. We used β-actin as a loading control. Solid line indicates where blot was cropped; however, all samples were run on the same gel and exposed simultaneously. Western blots displayed are representative of n > 3 repeats. (B) Total TBK1 expression in murine PDA tumors relative to normal pancreas from non–tumor-bearing littermate controls. Total IRF3 was used as a loading control. Intensity quantification is representative of mean ±SEM. *P < 0.05 by unpaired, 2-tailed t test.

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