Melatonin and exosomes in ovarian cancer: investigation of the transcriptomic content (mRNAs and microRNAs) of tumour-derived extracellular vesicles and the redox potential of mesenchymal stem cells

Ovarian cancer (OC) is an alarming disease, characterized by the highest mortality rate among gynecological cancers due to its frequent late diagnosis. In advanced stages, this cancer exhibits chemoresistance to conventional therapies, highlighting the need to identify new treatments. This scenario is exacerbated by the tumor microenvironment, which consists of multiple cell populations with varying degrees of malignancy, capable of communicating with other cells via extracellular vesicles (e.g., exosomes) that can induce differentiation in other cells through their contents. Thus, mesenchymal stem cells, particularly those derived from adipose tissue (AD-MSCs), play an important role in the progression of OC by acquiring a malignant phenotype following exosome action, thereby exacerbating aggressiveness and facilitating the acquisition of chemoresistance. In this context, melatonin-an indoleamine produced by the pineal gland-has shown promise as a potential therapy due to its immunomodulatory, pro-oxidative effects on tumors, and pro-apoptotic properties. Thus, the present study aims to investigate the action of melatonin in an in vitro CO model (SKOV-3 and OVCAR-3 cell lines) and the effects of exosomes secreted by these tumor cells-whether or not treated with melatonin-on AD-MSCs. Cytotoxicity, invasion, and cell migration assays, as well as oxidative stress and antioxidant capacity assays, will be performed on AD-MSCs to understand how exosomes modulate its oncogenic transformation. In addition, multiplex assays to analyze molecules related to tumor aggressiveness will be conducted on all cell lines and in exosome lysates. Transcriptomic mapping of mRNAs and microRNAs will be performed on exosomal content derived from tumor cells to study the influence of melatonin on the tumor gene signature and to identify the molecules delivered to AD-MSCs. Thus, this research project aims to evaluate the effects of melatonin on CO cells and its modulatory capacity in AD-MSCs, in order to better understand the mechanisms involved in ovarian tumor progression and to investigate a potential therapeutic approach.