A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis
Jacob P Hoj1, Benjamin Mayro1, Ann Marie Pendergast1
1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Abstract:
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.
Insights
Researchers discovered a signaling loop involving ABL2, AXL, and TAZ crucial for lung cancer brain metastasis. Inhibiting this pathway significantly reduced brain tumors, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Brain metastases are a severe complication of advanced lung cancer, leading to poor outcomes.
- Current treatments for brain metastases are limited by a lack of effective therapeutic targets and poor drug penetration across the blood-brain barrier (BBB).
Purpose of the Study:
- To identify and characterize novel molecular pathways driving lung adenocarcinoma brain metastasis.
- To explore the potential of targeting identified pathways for therapeutic intervention against brain metastases.
Main Methods:
- Investigated the role of the TAZ transcriptional co-activator in lung adenocarcinoma brain metastasis.
- Utilized gene expression analysis to identify transcripts enriched in brain metastases.
- Examined the signaling interactions between TAZ, ABL2, and AXL using molecular and cellular assays.
- Assessed the efficacy of ABL inhibitors and gene knockdown strategies in preclinical models.
Main Results:
- Identified an autocrine signaling axis involving TAZ, ABL2, and AXL essential for brain metastasis colonization.
- Demonstrated that nuclear TAZ accumulation drives the expression of ABL2 and AXL.
- Showed that ABL2 activation promotes TAZ phosphorylation and nuclear localization, forming a feed-forward loop.
- Found that inhibiting ABL or knocking down ABL2, AXL, or TAZ significantly reduced brain metastases.
Conclusions:
- The AXL-ABL2-TAZ signaling loop is a critical driver of lung adenocarcinoma brain metastasis.
- Targeting this pathway with inhibitors, such as ABL and AXL inhibitors, holds therapeutic promise for treating brain metastases.
