Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Victoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, Rolf A. Brekken
Victoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, Rolf A. Brekken
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Research Article Oncology

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

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 7

Reexpression of Tbk1 partially reverses colonization deficit in Tbk1Δ/ΔKIC cells.

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Reexpression of Tbk1 partially reverses colonization deficit in Tbk1Δ/ΔK...
(A) Protein lysates from Tbk1Δ/ΔKIC and Tbk1+/+KIC cell lines infected with pCDH–empty vector (EV) or pCDH-TBK1 (T) were immunoblotted for TBK1. 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. (B) Representative images of Tbk1Δ/ΔKIC-C cells infected with EV or T plated on a mixed layer of collagen and Matrigel. Cells were fixed and nuclei were labeled with DAPI (show in blue); F-actin was labeled with phalloidin (red). (C) Representative images of lungs and H&E (original magnification, ×20) from NOD/SCID mice sacrificed 7 days after i.v. injection with Tbk1KIC EV and T cell lines (100,000 cells injected per mouse, n = 4–5 mice/group). (D) Number of tumor nodules from C. (E) Lung weights from C. Results are representative of mean ±SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple-comparisons test.