The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
Open accessAbstract
In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)(low) signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.
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“TGF-β2 was reported to contribute to metastatic tumor dormancy333–335”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [334]
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Metadata
- Authors
- Bragado, P., Estrada, Y., Parikh, F., Krause, S., Capobianco, C., Farina, H. G., Schewe, D. M., & Aguirre-Ghiso, J. A.
- Affiliations
- Tisch Cancer Institute (US)
- University Hospital Schleswig-Holstein (DE)
- National University of Quilmes (AR)
- Venue
- Nature Cell Biology
- Published
- 2013-10-27
- Volume
- 15
- Issue
- 11
- Pages
- 1351-1361
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4006312
- OpenAlex
- W2163472474
- Cited by
- 503
- References
- 55
- Citations by year
- 2026: 36 · 2025: 30 · 2024: 50 · 2023: 44 · 2022: 44 · 2021: 75 · 2020: 43 · 2019: 35 · 2018: 39 · 2017: 35 · 2016: 31 · 2015: 23 · 2014: 18
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- New York State Stem Cell Science
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Deutsche Krebshilfe
- National Cancer Institute (CA109182, U54CA163131, CA163131, R01CA109182)
- National Institute of Environmental Health Sciences (R21ES017146, ES017146)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- disseminated tumor cells, TGF-beta2, p38 MAPK, head and neck squamous cell carcinoma, tumor dormancy, bone marrow microenvironment, lung metastasis, seed and soil hypothesis, Smad1/5, p27, CDK4
- MeSH terms
- Animals, Enzyme Activation, Mice, Nude, Neoplasms, Experimental, Proteoglycans, Signal Transduction, Receptors, Transforming Growth Factor beta, Cell Lineage, p38 Mitogen-Activated Protein Kinases, Mice, Transforming Growth Factor beta2, Tumor Microenvironment
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