Abstract A098: Microenvironment-regulated matrix Gla protein drives ovarian cancer stemness

Abstract

Abstract The clinical evolution of ovarian cancer (OC), with peritoneal dissemination, tumor relapse and chemoresistance, seems to be accounted for by a small population of ovarian cancer stem cells (OCSC), thus making them an attractive target for more efficacious treatments. However, this could only be achieved through the detailed characterization of the molecular and functional traits of this elusive cell subpopulation. Therefore, the identification of novel OCSC-associated targets and therapeutic approaches may offer alternative treatment options. We established a new platform of patient-derived organotypic models of OC and found that Matrix Gla Protein (MGP) was upregulated in cancer cells upon contact with the peritoneal tumor microenvironment. MGP is classically known as a vitamin K-dependent calcium chelator, mainly associated with the inhibition of tissue calcification and cardiovascular disease. In addition, MGP is also aberrantly expressed in different cancer types, but the biological mechanisms that regulate its functional contribution to cancer progression is still unknown. Our transcriptomic profiling of primary OCSC versus their non-stem counterpart pointed to MGP as a potential driver of cancer stemness. Indeed, we obtained evidence that MGP promotes, and is required for, stemness-associated biological features in vitro and in animal models, including sphere formation and tumor initiation. MGP was also implicated in the regulation of the expression of several key genes involved in stemness and/or EMT. Finally, MGP was upregulated in OC patients following chemotherapy, suggesting that the protein may be involved in OCSC-driven chemoresistance. The molecular mechanisms underlying MGP-regulated OCSC pathophysiology were investigated by RNA sequencing experiments on MGP-manipulated OC cells, which unveiled genetic networks and pathways that are orchestrated by MGP to promote OCSC function. The biological role of MGP in OC provides novel insight into the biology of OCSC, thus defining new pathways involved in OC stemness and paving the way to innovative therapeutic strategies for OC eradication. Citation Format: Valentina Nieddu, Valentina Melocchi, Chiara Battistini, Giulia Franciosa, Michela Lupia, Jesper Olsen, Nicoletta Colombo, Fabrizio Bianchi, Ugo Cavallaro. Microenvironment-regulated matrix Gla protein drives ovarian cancer stemness [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A098.