2. Academic Validation
  3. Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

  • Cancer Cell. 2021 Jan 11;39(1):68-82.e9. doi: 10.1016/j.ccell.2020.10.012.
Ilaria Guccini 1,  Ajinkya Revandkar 2,  Mariantonietta D'Ambrosio 3,  Manuel Colucci 3,  Emiliano Pasquini 2,  Simone Mosole 2,  Martina Troiani 2,  Daniela Brina 2,  Raheleh Sheibani-Tezerji 4,  Angela Rita Elia 2,  Andrea Rinaldi 2,  Nicolò Pernigoni 2,  Jan Hendrik Rüschoff 5,  Susanne Dettwiler 5,  Angelo M De Marzo 6,  Emmanuel S Antonarakis 7,  Costanza Borrelli 8,  Andreas E Moor 8,  Ramon Garcia-Escudero 9,  Abdullah Alajati 2,  Giuseppe Attanasio 2,  Marco Losa 10,  Holger Moch 5,  Peter Wild 11,  Gerda Egger 12,  Andrea Alimonti 13
Affiliations

Affiliations

  • 1 Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Institute of Molecular Health Sciences, ETH Zurich, Zurich 8093, Switzerland.
  • 2 Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Università della Svizzera Italiana, Lugano 6900, Switzerland.
  • 3 Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne 1011, Switzerland; Università della Svizzera Italiana, Lugano 6900, Switzerland.
  • 4 Ludwig Boltzmann Institute Applied Diagnostics, 1090 Vienna, Austria.
  • 5 Department of Pathology and Molecular Pathology, University Hospital Zurich (USZ), Zurich 8091, Switzerland.
  • 6 Departments of Pathology, Urology and Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 7 Departments of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 8 Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland.
  • 9 Molecular Oncology Unit, CIEMAT, Madrid 28040, Spain; Biomedicine Research Institute, Hospital 12 Octubre, Madrid 28041, Spain; CIBERONC, Madrid 28029, Spain.
  • 10 Anatomical Pathology Specialization Unit, Toma Advanced Biomedical Assay, Busto Arsizio 21052, Italy.
  • 11 Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, 60596 Frankfurt Am Main, Germany; Frankfurt Institute for Advanced Studies (FIAS), Frankfurt 60438, Germany.
  • 12 Ludwig Boltzmann Institute Applied Diagnostics, 1090 Vienna, Austria; Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
  • 13 Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Università della Svizzera Italiana, Lugano 6900, Switzerland; Department of Medicine, University of Padua, Padua 35128, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, Zurich 8093, Switzerland. Electronic address: andrea.alimonti@ior.usi.ch.
PMID: 33186519 DOI: 10.1016/j.ccell.2020.10.012
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.

Keywords

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

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