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 Alajati; Giuseppe Attanasio; Marco Losa; Holger Moch; Peter Wild; Gerda Egger; Andrea Alimonti

doi:10.1016/j.ccell.2020.10.012

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

2 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 language	English (US)
Pages (from-to)	68-82.e9
Journal	Cancer cell
Volume	39
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2020.10.012
State	Published - Jan 11 2021

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2020.10.012

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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., ... Alimonti, A. (2021). Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis. Cancer cell, 39(1), 68-82.e9. https://doi.org/10.1016/j.ccell.2020.10.012

Guccini, I, Revandkar, A, D'Ambrosio, M, Colucci, M, Pasquini, E, Mosole, S, Troiani, M, Brina, D, Sheibani-Tezerji, R, Elia, AR, Rinaldi, A, Pernigoni, N, Rüschoff, JH, Dettwiler, S, De Marzo, AM, Antonarakis, ES, Borrelli, C, Moor, AE, Garcia-Escudero, R, Alajati, A, Attanasio, G, Losa, M, Moch, H, Wild, P, Egger, G & Alimonti, A 2021, 'Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis', Cancer cell, vol. 39, no. 1, pp. 68-82.e9. https://doi.org/10.1016/j.ccell.2020.10.012

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title = "Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis",

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",

author = "Ilaria Guccini and Ajinkya Revandkar and Mariantonietta D'Ambrosio and Manuel Colucci and Emiliano Pasquini and Simone Mosole and Martina Troiani and Daniela Brina and Raheleh Sheibani-Tezerji and Elia, {Angela Rita} and Andrea Rinaldi and Nicol{\`o} Pernigoni and R{\"u}schoff, {Jan Hendrik} and Susanne Dettwiler and {De Marzo}, {Angelo M.} and Antonarakis, {Emmanuel S.} and Costanza Borrelli and Moor, {Andreas E.} and Ramon Garcia-Escudero and Abdullah Alajati and Giuseppe Attanasio and Marco Losa and Holger Moch and Peter Wild and Gerda Egger and Andrea Alimonti",

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doi = "10.1016/j.ccell.2020.10.012",

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T1 - Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

AU - Guccini, Ilaria

AU - Revandkar, Ajinkya

AU - D'Ambrosio, Mariantonietta

AU - Colucci, Manuel

AU - Pasquini, Emiliano

AU - Mosole, Simone

AU - Troiani, Martina

AU - Brina, Daniela

AU - Sheibani-Tezerji, Raheleh

AU - Elia, Angela Rita

AU - Rinaldi, Andrea

AU - Pernigoni, Nicolò

AU - Rüschoff, Jan Hendrik

AU - Dettwiler, Susanne

AU - De Marzo, Angelo M.

AU - Antonarakis, Emmanuel S.

AU - Borrelli, Costanza

AU - Moor, Andreas E.

AU - Garcia-Escudero, Ramon

AU - Alajati, Abdullah

AU - Attanasio, Giuseppe

AU - Losa, Marco

AU - Moch, Holger

AU - Wild, Peter

AU - Egger, Gerda

AU - Alimonti, Andrea

PY - 2021/1/11

Y1 - 2021/1/11

N2 - 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.

AB - 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.

KW - FGF1

KW - GDF-15

KW - MMPs

KW - PTEN

KW - TIMP1

KW - docetaxel

KW - prostate cancer metastasis

KW - senescence

KW - senescence-associated secretory phenotype (SASP)

KW - senolytic therapy

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DO - 10.1016/j.ccell.2020.10.012

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C2 - 33186519

AN - SCOPUS:85096882552

SN - 1535-6108

VL - 39

SP - 68-82.e9

JO - Cancer cell

JF - Cancer cell

IS - 1

ER -

Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Abstract

Keywords

ASJC Scopus subject areas

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