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A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis.

Publication ,  Journal Article
Hoj, JP; Mayro, B; Pendergast, AM
Published in: Cell Rep
December 10, 2019

Brain metastases are a common consequence of advanced lung cancer, resulting in cranial neuropathies and increased mortality. Currently, there are no effective therapies to treat brain metastases due to a lack of actionable targets and a failure of systemic therapies to penetrate the blood-brain barrier (BBB). Here we identify an autocrine signaling axis required for lung adenocarcinoma brain metastasis, whereby nuclear accumulation of the TAZ transcriptional co-activator drives expression of a panel of transcripts enriched in brain metastases, including ABL2 and AXL, encoding for protein tyrosine kinases that engage in bidirectional signaling. Activation of ABL2 in turn promotes TAZ tyrosine phosphorylation and nuclear localization, establishing an autocrine AXL-ABL2-TAZ feed-forward signaling loop required for brain metastasis colonization. Notably, treatment with a BBB-penetrant ABL allosteric inhibitor or knockdown of ABL2, AXL, or TAZ markedly decreases brain metastases. These findings suggest that ABL and AXL inhibitors might be effective against brain metastases.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

December 10, 2019

Volume

29

Issue

11

Start / End Page

3421 / 3434.e8

Location

United States

Related Subject Headings

  • Transcription Factors
  • Signal Transduction
  • Receptor Protein-Tyrosine Kinases
  • Pyrazoles
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Protein Kinase Inhibitors
  • Niacinamide
  • Mice
  • Lung Neoplasms
 

Citation

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Hoj, J. P., Mayro, B., & Pendergast, A. M. (2019). A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis. Cell Rep, 29(11), 3421-3434.e8. https://doi.org/10.1016/j.celrep.2019.11.018
Hoj, Jacob P., Benjamin Mayro, and Ann Marie Pendergast. “A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis.Cell Rep 29, no. 11 (December 10, 2019): 3421-3434.e8. https://doi.org/10.1016/j.celrep.2019.11.018.
Hoj JP, Mayro B, Pendergast AM. A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis. Cell Rep. 2019 Dec 10;29(11):3421-3434.e8.
Hoj, Jacob P., et al. “A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis.Cell Rep, vol. 29, no. 11, Dec. 2019, pp. 3421-3434.e8. Pubmed, doi:10.1016/j.celrep.2019.11.018.
Hoj JP, Mayro B, Pendergast AM. A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis. Cell Rep. 2019 Dec 10;29(11):3421-3434.e8.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

December 10, 2019

Volume

29

Issue

11

Start / End Page

3421 / 3434.e8

Location

United States

Related Subject Headings

  • Transcription Factors
  • Signal Transduction
  • Receptor Protein-Tyrosine Kinases
  • Pyrazoles
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Protein Kinase Inhibitors
  • Niacinamide
  • Mice
  • Lung Neoplasms