Characterization of NOTCH signalling pathway in PTEN-deficient prostate tumorigenesis


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PhD thesis: a PhD thesis.
Characterization of NOTCH signalling pathway in PTEN-deficient prostate tumorigenesis
Revandkar Ajinkya
Alimonti Andrea
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Université de Lausanne, Faculté de biologie et médecine
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RésuméProstate cancer is a commonly diagnosed non-cutaneous malignancy and one of the leading
causes of cancer-related deaths in men. Particularly, advanced prostate cancer is considered of
high-risk with poor prognosis and survival. Several studies have identified that activation
NOTCH pathway is associated with advanced stage of the disease and therapy-resistance in
patients. However, the mechanism by which NOTCH pathway is activated in prostate cancer
still remains unknown. Moreover, preclinical studies determining the therapeutic efficacy of
NOTCH pathway inhibitors in prostate cancer is lacking. Here, in this study we show that loss
of PTEN, a frequently altered tumour suppressor gene in prostate cancer, upregulates the
expression of ADAM17, thereby activating NOTCH signalling in prostate tumours.
Mechanistically, loss of PTEN triggers the accumulation of an oncogenic isoform of the
transcription factor CUX1 that favours ADAM17 transcription. Notably, over-expression of the
oncogenic isoform of CUX1 (p110 CUX1) both in vitro and in vivo resulted in up-regulation
of ADAM17 and activation of 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 demonstrate that pharmacological inhibition of
Notch pathway using g-secretase inhibitor promotes growth arrest and restricts tumourinvasiveness
in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular
Taken together, our study describes a novel pro-tumorigenic network that links PTEN-loss
to ADAM17 and NOTCH signalling in a PI3K-independent manner, thus providing the
rationale for the use of NOTCH pathway inhibitors in advance prostate cancer patients.

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31/01/2019 10:48
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20/08/2019 14:04
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