Seminar

The characterization of a novel type of cellular senescence response which is elicited by complete loss of the tumor suppressor PTEN

Andrea Alimonti, PhD

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 the immune response (referred as to 'senescence surveillance’)2-4. However, whether this is a common feature of different types of senescence, still remains elusive5. Here we show that Pten loss induced cellular senescence (PICS)6, contrary to OIS, opposes tumourigenesis in absence of activation of the immune system and tumour 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. Taken together, our data demonstrate that senescence surveillance in pre-malignant senescence tumours can be blocked by the 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.