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Reactivation of senescence surveillance in Pten loss induced cellular senescence

Toso, Alberto and Proietti, Michelle and Revandkar, Ajinkya and Zhang, Jiangwen and Guccini, Ilaria and Sarti, Manuela and Pinton, Sandra and Marini, Camilla and Scanziani, Eugenio and Catapano, Carlo and Pandolfi, Pier Paolo and Grassi, Fabio and Alimonti, Andrea (2014) Reactivation of senescence surveillance in Pten loss induced cellular senescence. Cell Reports.

Abstract

Aberrant activation of oncogenes or down regulation of tumour suppressor genes trigger a premature senescence program that acts as an intrinsic tumour suppressive mechanism in vivo1. Oncogene-induced senescence (OIS) is reported to induce tumour clearance by promoting the activation of an anti-tumour immune response (referred as to ‘senescence surviliance’)2-4. However, whether this is a common feature of different types of senescence
responses, still remains elusive5. Here we show that Pten loss induced cellular senescence

(PICS)6, contrary to OIS, opposes tumourigenesis in absence of immune-mediated clearance. Indeed, we find that in PICS senescence surveillance is impaired by a senescence independent cytokine network orchestrated by activation of the signal transducer and activator of transcription 3 (Stat3). Strikingly, genetic inactivation of Stat3 in the mouse prostate epithelium reprograms the senescence associated secretory phenotype (SASP) of PICS restoring senescence surveillance. To this end, pharmacological inhibition of the Jak/Stat3 pathway, also triggers an immune response, thereby activating tumour clearance. Notably, we found that Stat3 activation in PICS is sustained by down-regulation of the protein tyrosine phosphatase (PTP) SHP2, providing evidence for the existence of a novel PTEN/SHP2 tumor suppressive axis. Taken together, our data demonstrate that senescence surveillance in pre- malignant senescence tumors can be blocked by activation of senescence independent pathways. Therefore the genetic background of senescent cells should be carefully considered in order to design more effective pro-senescence therapies for cancer.

Item Type: Article
Date Deposited: 04 May 2016 23:45
Last Modified: 04 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/8868

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