Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Ilaria Guccini, Ajinkya Revandkar, Mariantonietta D'Ambrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Daniela Brina, Raheleh Sheibani-Tezerji, Angela Rita Elia, Andrea Rinaldi, Nicolò Pernigoni, Jan Hendrik Rüschoff, Susanne Dettwiler, Angelo M. De Marzo, Emmanuel S. Antonarakis, Costanza Borrelli, Andreas E. Moor, Ramon Garcia-Escudero, Abdullah AlajatiGiuseppe Attanasio, Marco Losa, Holger Moch, Peter Wild, Gerda Egger, Andrea Alimonti

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)68-82.e9
JournalCancer Cell
Volume39
Issue number1
DOIs
StatePublished - Jan 11 2021
Externally publishedYes

Bibliographical note

Funding Information:
We acknowledge all the members of Alimonti lab and IOR/IRB institutes. This work was supported by ERC consolidator (683136), a Swiss Cancer League (KFS4267-08-2017) grant, the Dr. Josef Steiner Foundation, a Swiss Card-Onco-Grant of Alfred and Annemarie von Sick grant, and the Helmut Horten Foundation, SNSF (310030_176045), PCUK (RIA15-ST2-018), and IBSA Foundation. Conceptualization, A.A. I.G. and A.R.; Writing ? Original Draft, A.A. I.G. and A.R.; In Vivo and In Vitro Experiments, I.G. A.R. M.C. M.D. E.P. G.A. N.P.D.B. and A.R.E.; Bioinformatics, M.T. and R.G.-E.; Clinical Samples, S.M. M.L. R.S.-T. G.E. J.H.R. S.D. H.M. P.W. A.M.D.M. and E.S.A.; smFISH, C.B. and A.E.M. A.A. is a cofounder of and owns stock in OncoSense and is an inventor of the patent WO2019142095A1. E.S.A. is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Eli-Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Constellation, Bristol-Myers Squibb, AstraZeneca, Clovis, and Merck; and he is the co-inventor of a patented biomarker technology that has been licensed to QIAGEN.

Funding Information:
We acknowledge all the members of Alimonti lab and IOR/IRB institutes. This work was supported by ERC consolidator ( 683136 ), a Swiss Cancer League ( KFS4267-08-2017 ) grant, the Dr. Josef Steiner Foundation , a Swiss Card-Onco-Grant of Alfred and Annemarie von Sick grant, and the Helmut Horten Foundation , SNSF ( 310030_176045) , PCUK ( RIA15-ST2-018 ), and IBSA Foundation .

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • FGF1
  • GDF-15
  • MMPs
  • PTEN
  • TIMP1
  • docetaxel
  • prostate cancer metastasis
  • senescence
  • senescence-associated secretory phenotype (SASP)
  • senolytic therapy

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