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Tumor Stroma-Derived TGF-β Limits Myc-Driven Lymphomagenesis via Suv39h1-Dependent Senescence
Open accessAbstract
Activated RAS/BRAF oncogenes induce cellular senescence as a tumor-suppressive barrier in early cancer development, at least in part, via an oncogene-evoked DNA damage response (DDR). In contrast, Myc activation-although producing a DDR as well-is known to primarily elicit an apoptotic countermeasure. Using the Emu-myc transgenic mouse lymphoma model, we show here in vivo that apoptotic lymphoma cells activate macrophages to secrete transforming growth factor beta (TGF-beta) as a critical non-cell-autonomous inducer of cellular senescence. Accordingly, neutralization of TGF-beta action, like genetic inactivation of the senescence-related histone methyltransferase Suv39h1, significantly accelerates Myc-driven tumor development via cancellation of cellular senescence. These findings, recapitulated in human aggressive B cell lymphomas, demonstrate that tumor-prompted stroma-derived signals may limit tumorigenesis by feedback senescence induction.
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“p53 cooperates with the NF- κB pathway to regulate SASP factors that can activate macrophages to form a tumour- suppressive microenvironment 147,148 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [147]
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“In an Eµ-Myc lymphoma model, p53induced apoptosis of lymphoma cells led to the activation of macrophages to secrete TGFß1, which in turn induced senescence in lymphoma cells 36”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [36]
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“Supporting this notion, the burden of senescent cells in tissues increases significantly with age in mice, primates, and humans,27 and they can be found in both benign and malignant tumours.31–35”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [34]
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“Since senescent cells are generally abundant in benign tumours and also present at low numbers in several malignancies,31–34,57 their paracrine activities could contribute to tumour progression and cancer metastasis.”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [34]
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Metadata
- Authors
- Reimann, M., Lee, S., Loddenkemper, C., Dörr, J. R., Tabor, V., Aichele, P., Stein, H., Dörken, B., Jenuwein, T., & Schmitt, C. A.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Max Delbrück Center (DE)
- University Medical Center Freiburg (DE)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Schmitt, Clemens A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 17
- Issue
- 3
- Pages
- 262-272
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2022861507
- Cited by
- 184
- References
- 57
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 11 · 2023: 12 · 2022: 9 · 2021: 12 · 2020: 17 · 2019: 6 · 2018: 9 · 2017: 14 · 2016: 11 · 2015: 10 · 2014: 10 · 2013: 15 · 2012: 12
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Max Planck Digital Library (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- TGF-beta, c-Myc, lymphomagenesis, cellular senescence, SUV39H1, histone methyltransferase, tumor stroma, macrophages, B-cell lymphoma, DNA damage response, apoptosis
- MeSH terms
- Animals, Lymphoma, Macrophage Activation, Macrophages, Methyltransferases, Mice, Transgenic, Repressor Proteins, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Proto-Oncogene Proteins c-myc, Cellular Senescence, Apoptosis, Mice
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