SPOT-011 Studying the implication of the RAS/MAPK and PI3K/AKT/TOR pathways in prostate cancer through an in vivo model of drosophila accessory glands tumorigenesis

IntroductionClinical studies have demonstrated that, in prostate cancer, Ras/MAPK and PI3K/AKT/TOR signalling pathways are often aberrantly co-activated in tumours, their activation levels increasing again in resistance phases. As these pathways are important for many fundamental processes (proliferation, cell growth or cell cycle), they are likely implicated in prostate tumorigenesis. However, the relative implication of each of these two pathways during prostate tumorigenesis, especially during the early phases, is not fully understood. Thus, we want to define the molecular mechanisms that are implicated in the co-deregulation of these pathways, and their possible implication in prostate cancer initiation and progression.Material and methodsWe propose and alternative in vivo model of prostate tumorigenesis in drosophila, where accessory glands are a functional equivalent of the human prostate. In this model, we can cumulate molecular modifications for both the considered pathways, and so study the impact of one on tumorigenesis.Results and discussionsOur results show that only the hyperactivation of the Ras/MAPK pathway in accessory glands can promote tumorigenesis, with production of cell masses that recapitulate many cancer hallmarks including uncontrolled cell growth and proliferation, enhanced matrix metalloproteinases expression, loss of expression of epithelial markers, neovascularisation-like tracheogenesis. However, both pathways are necessary to tumorigenesis, but they display different roles: the Ras/MAPK pathway is activated earlier and is able to recruit the PI3K/AKT/TOR pathway. Furthermore, we have shown that tumour formation in the accessory glands relies on an overproduction of Epidermal Growth Factor, EGF, which is known to be expressed at abnormally high levels in prostate cancer.ConclusionWe have developed a Drosophila model that displays many phenomena that are described in human prostate tumorigenesis. We now want to decipher which molecular mechanisms are implicated in the PI3K/AKT/TOR pathway activation. Then, we want to evaluate the pertinence of our findings in the human pathology, by the use of human biopsy samples: our aim is to transfer our results to new therapeutic applications, as the discovery of new mechanisms could allow definition of new biomarkers and eventually of new therapeutic targets.