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Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis
Open accessAbstract
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.
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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 (9, 23–25).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [23]
In the citing paper
“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).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [23]
In the citing paper
“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).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [23]
In the citing paper
“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).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [23]
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Metadata
- 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)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-15
- Volume
- 112
- Issue
- 26
- Pages
- E3402-11
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4491775
- 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
- Update notices
- correction (2024-01-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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 › Oncology › 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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