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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis

Chunlai Li1, Shouyu Wang1, Zhen Xing1

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Nature Cell Biology
|January 24, 2017
PubMed

Insights

Breast cancer bone metastasis is driven by crosstalk between ROR1-HER3 and Hippo-YAP pathways, regulated by long noncoding RNA. This mechanism offers potential therapeutic targets for bone metastasis and resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Bone metastases represent a significant challenge in breast cancer treatment due to limited therapeutic strategies.
  • Understanding the molecular mechanisms driving bone metastasis is crucial for developing effective interventions.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which breast cancer promotes bone metastasis.
  • To investigate the crosstalk between the ROR1-HER3 and Hippo-YAP pathways in the context of bone metastasis.
  • To identify potential therapeutic targets for treating bone metastasis and therapy-resistant breast cancers.

Main Methods:

  • Investigated the role of the orphan receptor tyrosine kinase ROR1 and its interaction with HER3.
  • Utilized molecular biology techniques to study the phosphorylation of HER3 at Tyr1307 and its downstream effects.
  • Analyzed the recruitment of RNA-protein complexes and their impact on the Hippo-YAP pathway.
  • Examined the methylation of Hippo/MST1 and its consequence on MST1 activity and YAP target gene expression.
  • Correlated the levels of ROR1, p-HER3 Tyr1307, and MAYA with clinical outcomes in patients with tumor metastasis.

Main Results:

  • ROR1 phosphorylates HER3 at Tyr1307 upon neuregulin stimulation, independent of other ErbB members.
  • Phosphorylated HER3 (p-HER3 Tyr1307) recruits the LLGL2-MAYA-NSUN6 complex, leading to Hippo/MST1 methylation at Lys59.
  • MST1 inactivation and subsequent YAP target gene activation promote osteoclast differentiation and bone metastasis.
  • Elevated levels of ROR1, p-HER3 Tyr1307, and MAYA are associated with increased tumor metastasis and poor patient prognosis.

Conclusions:

  • The study reveals a novel mechanism of breast cancer bone metastasis involving ROR1-HER3 and Hippo-YAP pathway crosstalk, dependent on long noncoding RNA.
  • This pathway activation leads to osteoclast differentiation and bone metastasis.
  • The findings highlight ROR1, p-HER3 Tyr1307, and MAYA as potential biomarkers and therapeutic targets for bone metastasis and therapy-resistant breast cancers.

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