Role of ERM proteins in Ovarian cancer development

LUJEA, NOELIA; MARTÍNEZ E; MARTINELLO M; MARTIN MASNER; ALCAIR W; KUNDA, PATRICIA; CABALIER ME; VILLATA A

Congreso; SAIB - SAMIGE Joint meeting 2021 on line November; 2021

Epithelial Ovarian Cancer (EOC) is a highly proliferative and metastatic malignancy. During EOC dissemination, cells that detach from the primary tumor are moved by the peritoneal fluid into the peritoneal cavity where, despite of being immersed in a liquid medium, they are capable of proliferate and aggregate to form tumor spheroids. Our goal is to understand the basic mechanisms of peritoneal metastasis, which might help to find diagnostic/prognostic tools that could allow the improvementof the therapeutic approach. We propose that the structural role of the ERM proteins (Ezrin/Radixin/Moesin), activated by phosphorylation (P-ERM), is key to ensuring cell survival, proliferation and tumor formation in peritoneal fluid. We used an in vitro model of spheroids generation in soft agar using SKOV-3 ovarian cancer cell line. We generated an Ezrin mutant with CRISPR-CAS9 system (Ezrin-/-) to evaluate the role of the ERM in spheroids formation. Through IF and microscopy experiments, we found that Ezrin-/- failed in forming spheroids in soft agar because cells are unable to divide. This phenotype could be rescue with ConA, a tetravalent lectin, suggesting that Ezrin may play a structural role that allow cells to proliferate and survive in soft environments. In order to evaluate the relationship between P-ERM and EOC development, we analyzed the intensity and distribution of P-ERM in human ovarian carcinoma samples provided by the Hospital Nacional de Clínicas of Córdoba, Argentina. This project has the approval from the HNC-CIEIS. The results showed that there is a difference in expression levels and distribution of P-ERM in relation to malignancy, being higher in invasive papillary carcinomas and lower in endometrioid carcinomas. We propose that the ERM proteins, activated by phosphorylation, play a crucial role in favoring the development of intraperitoneal metastasis and their activation is positively related to malignancy, therefore they could be evaluated as a potential EOC biomarker.