Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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

×

Figure 7

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

Options: View larger image (or click on image) Download as PowerPoint
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.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts