Cited by 103Hippo pathway signaling and YAP/TAZSarcoma Diagnosis and TreatmentCancer-related molecular mechanisms research

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

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Eisinger-Mathason, T. S. Karin, Mucaj, Vera, Biju, Kevin M., Nakazawa, Michael S., Gohil, Mercy, Cash, Timothy P., Yoon, Sam S., Skuli, Nicolas +3 more·2015·Proceedings of the National Academy of Sciences

Abstract

Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

Integrity signals

Registry

Crossref · 10.1073/pnas.1420005112

Cites

51 of 51 references verified0 citation errors · 0 not checkable

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  • In DDLS, UPS, and MFS, the Hippo pathway is frequently deregulated through increased expression of the transcriptional coactivators YAP and TAZ.

    “In DDLS, UPS, and MFS, the Hippo pathway is frequently deregulated through increased expression of the transcriptional coactivators YAP and TAZ (9, 23–25).”
  • YAP and TAZ are paralogs that share similar functions and oncogenic activation in multiple tumor types, including breast and liver cancer and various soft tissue sarcomas including DDLS, MFS, and UPS.

    “The Hippo effectors YAP and TAZ are paralogs that share similar functions and oncogenic activation in multiple tumor types, including breast and liver cancer and various soft tissue sarcomas including DDLS, MFS, and UPS (9, 23, 24).”
  • Prior studies show that Hippo pathway deregulation promotes tumorigenesis in WD/DDLS, MFS, and UPS through activation of YAP and TAZ.

    “This evidence supporting the importance of YAP and TAZ in driving WD/DDLS, MFS, and UPS is bolstered by prior studies showing that Hippo pathway deregulation promotes tumorigenesis in these sarcoma types through activation of YAP and TAZ (23, 24).”
  • Overactivity of YAP and TAZ has been implicated in the formation of embryonal and alveolar rhabdomyosarcoma, myxoid liposarcoma, fibrosarcoma, leiomyosarcoma, and synovial sarcoma.

    “Overactivity of YAP and TAZ has also been implicated in the formation of embryonal and alveolar rhabdomyosarcoma, myxoid liposarcoma, fibrosarcoma, leiomyosarcoma, and synovial sarcoma (23, 45–47).”

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Authors
Eisinger-Mathason, T. S. K., Mucaj, V., Biju, K. M., Nakazawa, M. S., Gohil, M., Cash, T. P., Yoon, S. S., Skuli, N., Park, K. M., Gerecht, S., & Simon, M. C.
Affiliations
  • Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
  • University of Pennsylvania (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Inserm (FR)
  • Johns Hopkins University (US)
  • Howard Hughes Medical Institute (US)
Venue
Proceedings of the National Academy of Sciences
Published
2015-06-15
Volume
112
Issue
26
Pages
E3402-11
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W1633738151
Cited by
103
References
51
Citations by year
2026: 1 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 22 · 2020: 10 · 2019: 9 · 2018: 10 · 2017: 8 · 2016: 12 · 2015: 3
FWCI
5.86
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Cancer Institute (F32 CA156979-01, T32 CA009140-36, F31 CA174211-01, R01 CA138265)
  • HHS | National Institutes of Health (U54CA143868)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
soft tissue sarcoma, Hippo signaling pathway, YAP, FOXM1, TEAD1, carcinogenesis, cell proliferation, transcriptional co-regulation, autochthonous mouse model, pharmacological inhibition, therapeutic target
MeSH terms
Forkhead Box Protein M1, Hippo Signaling Pathway, YAP-Signaling Proteins, Humans, Phosphoproteins, Sarcoma, Transcription Factors, Protein Serine-Threonine Kinases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Forkhead Transcription Factors, Carcinogenesis

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