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  • Enhancing chemotherapy effi...
    Toso, Alberto; Revandkar, Ajinkya; Di Mitri, Diletta; Guccini, Ilaria; Proietti, Michele; Sarti, Manuela; Pinton, Sandra; Zhang, Jiangwen; Kalathur, Madhuri; Civenni, Gianluca; Jarrossay, David; Montani, Erica; Marini, Camilla; Garcia-Escudero, Ramon; Scanziani, Eugenio; Grassi, Fabio; Pandolfi, Pier Paolo; Catapano, Carlo V; Alimonti, Andrea

    Cell reports, 10/2014, Letnik: 9, Številka: 1
    Journal Article

    Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of the protein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.