Abstract 1891: Oncogenic MDM2-containing exosomes promote pre-metastatic niche establishment

Abstract

Abstract Extracellular vesicles (EVs) have an important role in the communication between cells for their ability to transfer proteins and other biologically active molecules. EVs have been also described to have unique functions during pre-metastatic niche establishment and maintenance. MDM2 oncoprotein is the best-characterized cellular antagonist of p53 and its amplification is one of the most known mechanisms for tumor development. MDM2 amplification occurs in more than forty different types of malignancies and in 100% of well-differentiated and dedifferentiated liposarcoma (DDLPS). Retroperitoneal DDLPS is especially concerning given its propensity for multifocal local and distant recurrence, accounting for an overall survival rate of 10% at 10 years. Here, we show the presence of MDM2 in tumor EVs and specifically in both DDLPS cell line-derived EVs and patient-serum EVs. We also show the ability of MDM2-cargo to be transferred to recipient preadipocytes. Furthermore, we also demonstrated that this transfer is able to promote a pre-metastatic niche establishment in the DDLPS tumor microenvironment fat bearing areas, inducing: (I) tumor associated phenotype such as enhanced proliferation and migration, in the recipient preadipocytes, by downregulation of MDM2 downstream pathway; (II) pro-inflammatory phenotype through the release of pro-inflammatory cytokines such as IL-8; (III) release of active metalloproteinases such as MMP2 which is crucial for the invasiveness of many disseminating tumors. In conclusion here we report the presence of MDM2, in the patient circulation; importantly showing that MDM2 triggers the release of active MMP-2, we also propose a possible mechanism for pre-metastatic niche establishment and DDLPS multifocal loco-regional recurrence. Citation Format: Lucia Casadei, Federica Calore, Ameya Deshmukh, Abeba Zewdu, Danielle A. Braggio, Paolo Fadda, Martin Wabitsch, Gonzalo Lopez, Jennifer Leight, Dina Lev, Carlo M. Croce, Raphael E. Pollock. Oncogenic MDM2-containing exosomes promote pre-metastatic niche establishment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1891.