Journal
CANCER CELL
Volume 39, Issue 1, Pages 68-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.10.012
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Funding
- ERC [683136]
- Swiss Cancer League grant [KFS4267-08-2017]
- Dr. Josef Steiner Foundation
- Swiss Card-Onco-Grant of Alfred and Annemarie von Sick grant
- Helmut Horten Foundation
- SNSF [310030_176045]
- PCUK [RIA15-ST2-018]
- IBSA Foundation
- Swiss National Science Foundation (SNF) [310030_176045] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [683136] Funding Source: European Research Council (ERC)
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Metastasis in prostate cancer is influenced by senescence with TIMP1 acting as a molecular switch. Elimination of senescent cells can impair tumor metastasis.
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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