ICSA2020 #icsa2020osaka

http://www.icsa2020-osaka.jp

**Postponed**

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Please save the new dates:

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June 7-10, 2021

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Members Featured Articles

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

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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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Featured Articles

Systemic overexpression of C-C motif chemokine ligand 2 promotes metabolic dysregulation and premature death in mice with accelerated aging

Fedra Luciano-Mateo, Noemí Cabré, Gerard Baiges-Gaya, Salvador Fernández-Arroyo, Anna Hernández-Aguilera, Elisabet Rodríguez-Tomàs, Meritxell Arenas, Jordi Camps, Javier A Menéndez, Jorge Joven

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Injection of tissues with senescent cells induces changes that mimic aging, and this process is delayed in mice engineered to eliminate senescent cells, which secrete proinflammatory cytokines, including C-C motif chemokine ligand 2 (Ccl2). Circulating levels of Ccl2 correlate with age, but the impact of Ccl2 on tissue homeostasis has not been established. We generated an experimental model by crossbreeding mice overexpressing Ccl2 with progeroid mice bearing a mutation in the lamin A (Lmna) gene. Wild-type animals and progeroid mice that do not overexpress Ccl2 were used as controls. Ccl2 overexpression decreased the lifespan of the progeroid mice and induced the dysregulation of glycolysis, the citric acid cycle and one-carbon metabolism in skeletal muscle, driving dynamic changes in energy metabolism and DNA methylation. This impact on cellular bioenergetics was associated with mitochondrial alterations and affected cellular metabolism, autophagy and protein synthesis through AMPK/mTOR pathways. The data revealed the ability of Ccl2 to promote death in mice with accelerated aging, which supports its putative use as a biomarker of an increased senescent cell burden and for the assessment of the efficacy of interventions aimed at extending healthy aging.

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