Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature
Open accessAbstract
Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.
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ECM stiffness triggers mechanotransduction pathways that influence tumor cell behavior, including activation of YAP/TAZ, FAK, and MAPK pathways and modulation of gene expression associated with proliferation, EMT, and drug resistance.
“However, beyond acting as a physical barrier, ECM stiffness also triggers mechanotransduction pathways that profoundly influence tumor cell behavior [91,92]. Mechanical cues generated by a stiffened matrix are sensed through integrin-based focal adhesions and transmitted via cytoskeletal tension to activate intracellular signaling cascades, including Yes-associated protein/Transcriptional coactiv”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [96]
The “Tumor Microenvironment Stiffness” section (page unavailable) says integrins sense ECM stiffness and that downstream FAK/SRC signaling activates YAP/TAZ. Its proposed consequence is primarily endothelial signaling and angiogenesis, not the claimed changes in tumor-cell behavior. The cited passages do not link stiffness to MAPK activation or to tumor-cell gene expression governing proliferation, EMT, and drug resistance; the mesenchymal transition discussed elsewhere is endothelial EndoMT. (LLM, conf=0.88)
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References 372 · Cited by 82
- Authors
- Hooglugt, A., van der Stoel, M. M., Boon, R. A., & Huveneers, S.
- Affiliations
- Amsterdam University Medical Centers (NL)
- Goethe University Frankfurt (DE)
- Corresponding author
- Huveneers, Stephan
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2021-02-04
- Volume
- 10
- Pages
- 612802-612802
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC7890025
- OpenAlex
- W3127191844
- Cited by
- 82
- References
- 372
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 17 · 2023: 14 · 2022: 11 · 2021: 12
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- YAP/TAZ signaling, endothelial cells, tumor angiogenesis, tumor vasculature, tumor microenvironment, hypoxia, vascular stiffness, lymphangiogenesis, vascular normalization, anti-angiogenic therapy, metastasis
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