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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

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Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

T S Karin Eisinger-Mathason1, Vera Mucaj1, Kevin M Biju1

  • 1Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;

Proceedings of the National Academy of Sciences of the United States of America
|June 17, 2015
PubMed

Insights

The Hippo pathway and Yes-Associated Protein (YAP) are deregulated in soft-tissue sarcomas. Targeting the transcription factor forkhead box M1 (FOXM1) shows promise for treating these cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Soft-tissue sarcomas are complex cancers with unknown genetic drivers.
  • Targeted therapies are urgently needed for effective treatment.

Purpose of the Study:

  • To investigate the role of the Hippo pathway and its effector Yes-Associated Protein (YAP) in soft-tissue sarcoma.
  • To identify novel therapeutic targets for sarcoma treatment.

Main Methods:

  • Analysis of human sarcoma patient data.
  • Development of a novel autochthonous mouse model for sarcoma.
  • Mechanistic studies to elucidate YAP and FOXM1 interactions.
  • Pharmacologic inhibition of FOXM1 in vivo.

Main Results:

  • The Hippo pathway is deregulated in soft-tissue sarcomas, leading to elevated YAP expression.
  • YAP-dependent forkhead box M1 (FOXM1) expression is crucial for proliferation in a subset of sarcomas.
  • FOXM1 directly interacts with the YAP/TEAD1 complex, co-regulating pro-proliferation genes.
  • Pharmacologic inhibition of FOXM1 reduced tumor size in vivo.

Conclusions:

  • FOXM1 is a key mediator of YAP-driven proliferation in soft-tissue sarcomas.
  • FOXM1 represents a promising therapeutic target for specific sarcoma subtypes.
Keywords:
FOXM1HippoYAPsarcoma

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