Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis
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Date
2021-01-11Type
- Journal Article
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Abstract
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. © 2020 Elsevier Show more
Publication status
publishedExternal links
Journal / series
Cancer CellVolume
Pages / Article No.
Publisher
Cell PressOrganisational unit
09711 - Moor, Andreas / Moor, Andreas
03739 - Stoffel, Markus / Stoffel, Markus
03739 - Stoffel, Markus / Stoffel, Markus
03630 - Krek, Wilhelm (ehemalig) / Krek, Wilhelm (former)
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Show all metadata
Citations
Cited 30 times in
Web of Science
Cited 30 times in
Scopus
ETH Bibliography
yes
Altmetrics