Telomerase Reactivation following Telomere Dysfunction Yields Murine Prostate Tumors with Bone Metastases
Open accessAbstract
To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
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In mouse models, continued telomere dysfunction can constrain cancer progression, whereas telomerase reactivation alleviates intratumoural DNA damage and leads to more aggressive tumour progression and metastasis.
“In mouse models, continued telomere dysfunction can constrain cancer progression, whereas telomerase reactivation alleviates intratumoural DNA damage and leads to more aggressive tumour progression and metastasis168.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [168]
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- Authors
- Ding, Z., Wu, C.-J., Jaskelioff, M., Ivanova, E., Kost-Alimova, M., Protopopov, A., Chu, G. C., Wang, G., Lu, X., Labrot, E. S., Hu, J., Wang, W., Xiao, Y., Zhang, H., Zhang, J., Zhang, J., Gan, B., Perry, S. R., Jiang, S., Li, L., Horner, J. W., Wang, Y. A., Chin, L., & DePinho, R. A.
- Affiliations
- Harvard University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Chin, Lynda
- DePinho, Ronald A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 148
- Issue
- 5
- Pages
- 896-907
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3629723
- OpenAlex
- W1984622067
- Cited by
- 220
- References
- 57
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 5 · 2020: 13 · 2019: 7 · 2018: 23 · 2017: 15 · 2016: 18 · 2015: 18 · 2014: 31 · 2013: 27 · 2012: 19
- FWCI
- 20.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (U01CA141508, K99CA194289, R01CA084628)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- telomerase reactivation, telomere dysfunction, prostate cancer, bone metastasis, PTEN, p53, SMAD4, TGF-beta signaling, genome rearrangement, tumor progression, DNA damage signaling, mouse tumor model
- MeSH terms
- Animals, Bone Neoplasms, Crosses, Genetic, Disease Models, Animal, Female, Humans, Male, Prostatic Neoplasms, Tumor Suppressor Protein p53, Telomere, Telomerase, Genomic Instability, Cell Line, Tumor, Mice, DNA Copy Number Variations
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