The association of perfluoroalkyl substances (PFAS) with fatty acid metabolism and ovarian cancer metastasis

Descrizione

Testo originale dell'annuncio (in inglese)

Forever chemicals, also known as poly- and perfluoroalkyl substances (PFAS), are a group of thousands of man-made chemicals used in manufacturing and various everyday products. They are nicknamed 'forever chemicals' because their unique chemical structures make them extremely difficult to break down. They can contaminate soil, surface water, and groundwater. In fact, several PFAS compounds have been detected in the blood of most U.S. adults. There is increasing concern about PFAS due to their potential to induce adverse health effects. Furthermore, PFAS structurally resemble fatty acids because both possess long hydrophobic carbon chains and terminal acidic functional groups, although PFAS contain fluorinated carbon chains. This raises concerns about their potential to disrupt normal lipid homeostasis, including the uptake, transport, and metabolism of fatty acids. This is particularly important because cancer cells often exhibit altered fatty acid metabolism to support rapid growth and survival. Moreover, recent data have indicated an association between higher PFAS plasma levels and poorer overall survival in patients with the most common and aggressive subtype of ovarian cancer (high-grade serous ovarian cancer, HGSC). HGSC remains the most lethal subtype of ovarian cancer. Ovarian cancer grows quickly and can progress from the early stages to advanced disease within a year. Therefore, the aim of this project is to test the hypothesis that PFAS facilitate the spread of HGSC by reprogramming metabolism towards fatty acid utilisation. To address key knowledge gaps in the field of the contribution of PFAS to HGSC dissemination, this proposal will combine in vitro and in vivo approaches. In Aim 1, we will verify whether the regulation of fatty acid metabolism by PFAS is a key pathway by which these compounds are involved in HGSC metastasis. In Aim 2, we will evaluate the in vivo effect of PFAS on the peritoneal invasion of HGSC cells and identify sites of cancer cell colonisation. We will assess the efficacy of pharmacological inhibitors in the presence or absence of PFAS. The overall aim of the proposed studies is to determine whether PFAS have the potential to alter the fatty acid metabolism of cancer cells and, via this pathway, stimulate cancer dissemination