Cell Polarity Distruption in Indolent RAS-mutated Follicle Cells Primes Aggressive Behaviours in Drosophila and Human Models of Ovarian Cancer

Serous ovarian cancers (SOC) are the most lethal gynaecological tumours. They are classified into lowgrade (LGSOC-10%) and high-grade (HGSOC-90%) subtypes, with HGSOC emerging as de novo malignant masses associated with TP53 aberrations, and LGSOC developing from pre-existing borderline lesions displaying RAS/MAPK mutations. No dedicated therapies are currently available for LGSOC, which undergo the same treatments as HGSOC but, given their indolent nature, barely respond to chemotherapy, and about 70% of women die from this disease. Despite most low-grade and highgrade ovarian tumours are clinically distinct, some hybrid serous cancer samples contain both low- and high-grade areas bearing the same RAS/MAPK founder mutation, suggesting a clonal relationship between the two histotypes. Since loss of apical-basal cell polarity is known to trigger aggressive phenotypes in epithelial cancers, we used a well-characterised Drosophila model of cooperative oncogenesis to address this question. We effectively demonstrate that loss of polarity in RAS-activated follicular cells is as sufficient as to induce locally aberrant phenotypes, accompanied by a number of systemic traits typical of severe ovarian cancers.