Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis
Open accessAbstract
Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.
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In prostate tumours with Pten-loss-induced senescence, genetic ablation of Timp1 operates as a switch favouring the development of metastases via effects on the function and relative abundance of certain SASP factors, such as MMPs, GDF-15, FGF1 and IGFBP5.
“Accordingly, in prostate tumours with Ptenloss- induced senescence, genetic ablation of Timp1 (encoding a metalloproteinase inhibitor factor) operates as a switch favouring the development of metastases via effects on the function and relative abundance of certain SASP factors, such as MMPs, GDF-15, FGF1 and IGFBP5 (ref. 170 ) .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [170]
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References 59 · Cited by 185
- Authors
- Guccini, I., Revandkar, A., D'Ambrosio, M., Colucci, M., Pasquini, E., Mosole, S., Troiani, M., Brina, D., Sheibani-Tezerji, R., Elia, A. R., Rinaldi, A., Pernigoni, N., Rüschoff, J. H., Dettwiler, S., De Marzo, A. M., Antonarakis, E. S., Borrelli, C., Moor, A. E., Garcia-Escudero, R., Alajati, A., Attanasio, G., Losa, M., Moch, H., Wild, P., Egger, G., & Alimonti, A.
- Affiliations
- ETH Zurich (CH)
- Institute of Oncology Research (CH)
- University Hospital Zurich (CH)
- Johns Hopkins University (US)
- Frankfurt Institute for Advanced Studies (DE)
- Ludwig Boltzmann Institute Applied Diagnostics (AT)
- University of Padua (IT)
- Corresponding author
- Alimonti, Andrea
- ORCID
- Guccini, Ilaria
- Colucci, Manuel
- Pasquini, Emiliano
- Mosole, Simone
- Brina, Daniela
- Sheibani-Tezerji, Raheleh
- Elia, Angela Rita
- Rinaldi, Andrea
- Pernigoni, Nicolò
- Rüschoff, Jan Hendrik
- Dettwiler, Susanne
- Antonarakis, Emmanuel S.
- Borrelli, Costanza
- Moor, Andreas E.
- Losa, Marco
- Moch, Holger
- Wild, Peter
- Egger, Gerda
- Alimonti, Andrea
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 39
- Issue
- 1
- Pages
- 68-82.e9
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W3100618950
- Cited by
- 185
- References
- 59
- Citations by year
- 2026: 33 · 2025: 49 · 2024: 35 · 2023: 29 · 2022: 27 · 2021: 10 · 2020: 1
- FWCI
- 9.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Krebsliga Schweiz (KFS4267-08-2017)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_176045)
- European Research Council (683136)
- Pancreatic Cancer UK (RIA15-ST2-018)
- Prostate Cancer UK
- Merck
- Helmut Horten Stiftung
- Dr. Josef Steiner Krebsstiftung
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- prostate cancer, TIMP-1, senescence-associated secretory phenotype, metastasis, PTEN loss, matrix metalloproteinases, senolytics, BCL-2 inhibitor, docetaxel resistance, chemotherapy-induced senescence
- MeSH terms
- Docetaxel, PC-3 Cells, Animals, Humans, Male, Neoplasm Metastasis, Neoplasm Transplantation, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Cellular Senescence, Gene Deletion, Tissue Inhibitor of Metalloproteinase-1, Matrix Metalloproteinases, PTEN Phosphohydrolase, Mice
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