ORAI3 loss drives neuroendocrine transdifferentiation of prostate cancer – AURORA

Calcium is a second messenger involved in various intracellular signaling pathways regulating proliferation, apoptosis, secretion and migration. These calcium signalings require in particular a fine regulation of the exchanges of calcium ions between the extracellular medium and the cytosol ensured by calcium channels of the plasma membrane. Different types of disturbances can nevertheless affect the physiological role of these channels. Indeed, for 15 years, researchers have identified ion channels involved in tumor progression. Prostate cancer (PCa) is the most common non-cutaneous human malignancy and third in terms of mortality in men (WHO 2021). Androgen-targeting therapies (anti-ADT) represent the first treatment options for localized PCa, along with surgery and radiotherapy. The vast majority of PCas become castration resistant after anti-ADT therapy and 20% of them evolve towards a neuroendocrine phenotype (PCa-NE). The survival rate for NE patients is low (30%), with a median survival of 9 to 36 months and few treatment options. Bioinformatics analyzes of public PCa-NE patient data have revealed its molecular signature. Surprisingly, we observed the negative regulation of a gene encoding a calcium channel: ORAI3. An unexpected result because we showed that ORAI3 is overexpressed in advanced PCa and participates in tumor cell proliferation and resistance to apoptosis (Dubois et al., 2014). I propose to study the role of ORAI3 loss in NE transdifferentiation and in the acquisition of metastatic properties. To do this, Omics approaches will be implemented using in vitro and in vivo models to identify the mechanisms mediated by ORAI3 and thus propose new combined treatment strategies against these aggressive forms of PCa.