Revandkar, Ajinkya Perciato, Maria Luna Toso, Alberto Alajati, Abdullah Chen, Jingjing Gerber, Hermeto Dimitrov, Mitko Rinaldi, Andrea Delaleu, Nicolas Pasquini, Emiliano D’Antuono, Rocco Pinton, Sandra Losa, Marco Gnetti, Letizia Arribas, Alberto Fraering, Patrick Bertoni, Francesco Nepveu, Alain Andrea Alimonti 2016-12-12 Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients. application/pdf https://susi.usi.ch/global/documents/319005 https://localhost:5000/ark:/12658/srd1319005 https://susi.usi.ch/documents/319005/files/Revandkar_NC_2016.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms13719 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319005 info:eu-repo/semantics/openAccess CC BY Nature communications. - 2016, vol. 7, p. 13719 Cancer genetics Prostate cancer info:eu-repo/classification/udc/61 Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence http://purl.org/coar/resource_type/c_6501