Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.
Cancer cell. 2024 Feb 29 [Epub]
Manuel Colucci, Sara Zumerle, Silvia Bressan, Federico Gianfanti, Martina Troiani, Aurora Valdata, Mariantonietta D'Ambrosio, Emiliano Pasquini, Angelica Varesi, Francesca Cogo, Simone Mosole, Cristina Dongilli, Maria Andrea Desbats, Liliana Contu, Ajinkya Revankdar, Jingjing Chen, Madhuri Kalathur, Maria Luna Perciato, Rossella Basilotta, Laczko Endre, Stefan Schauer, Alaa Othman, Ilaria Guccini, Miriam Saponaro, Luisa Maraccani, Nicolò Bancaro, Ping Lai, Lei Liu, Nicolò Pernigoni, Federico Mele, Sara Merler, Lloyd C Trotman, Greta Guarda, Bianca Calì, Monica Montopoli, Andrea Alimonti
Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Università della Svizzera Italiana, CH6900 Lugano, Switzerland; Faculty of Biology and Medicine, University of Lausanne UNIL, CH1011 Lausanne, Switzerland., Veneto Institute of Molecular Medicine (VIMM) & Department of Medicine, University of Padova, Padova, Italy., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Università della Svizzera Italiana, CH6900 Lugano, Switzerland; Veneto Institute of Molecular Medicine (VIMM) & Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Università della Svizzera Italiana, CH6900 Lugano, Switzerland; Bioinformatics Core Unit, Swiss Institute of Bioinformatics, TI, Bellinzona, Switzerland., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Department of Health Sciences and Technology (D-HEST) ETH Zurich, Zurich, CH, Switzerland., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; MRC London Institute of Medical Sciences (LMS), London, UK., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Università della Svizzera Italiana, CH6900 Lugano, Switzerland., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Children's GMP, LLC, St. Jude Children's Research Hospital, 262 Danny Thomas Place Mail Stop 920 Memphis, TN 38105, USA., School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK., Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 viale Ferdinando D'Alcontres, Italy., Functional Genomics Center Zurich, ETHZ and University of Zurich, Zurich, CH, Switzerland., Department of Health Sciences and Technology (D-HEST) ETH Zurich, Zurich, CH, Switzerland., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Veneto Institute of Molecular Medicine (VIMM) & Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy., Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland., Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust, Verona, Italy., Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA., Veneto Institute of Molecular Medicine (VIMM) & Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy., Institute of Oncology Research (IOR), CH6500 Bellinzona, Switzerland; Università della Svizzera Italiana, CH6900 Lugano, Switzerland; Veneto Institute of Molecular Medicine (VIMM) & Department of Medicine, University of Padova, Padova, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, Zurich, CH, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland. Electronic address: .