Abstract A054: Oncogenic functions of alternatively spliced <i>MDM2-ALT2</i> isoform in retroperitoneal liposarcoma

Abstract Retroperitoneal liposarcoma (RPLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS). Complete surgical resection remains the mainstay treatment while the high rate of locoregional recurrence constitutes the predominant cause of mortality. Well- differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are the most frequent subtypes of RPLPS and present amplified MDM2 gene as a hallmark. However, there are few reports evaluating the role of alternatively spliced MDM2 transcripts in RPLPS. In this study, we assessed MDM2-ALT2 expression levels in a cohort of RPLPS patients and evaluated biological functions of MDM2-ALT2 isoform in vitro in DDLPS cell lines. Using BaseScope™ and qPCR, we demonstrated that MDM2-Full Length (MDM2-FL) and MDM2-ALT2 expression levels were upregulated in RPLPS patient-derived tissue samples compared to normal adjacent to tumor tissue (NAT). DDLPS cells overexpressing MDM2-FL or MDM2-ALT2 had higher proliferation rates and increased migration and invasion capacities, as well as increased protein levels of p- AKT, mTOR, p70S6K, MMP2 and cJun. Simultaneous overexpression of MDM2-ALT2 and AKT silencing showed that AKT inhibition impaired p-p70S6K and MMP2 protein increased levels and led to significantly decreased proliferation and migration rates compared to cells overexpressing MDM2-ALT2 only. Taken together, our data suggest that MDM2-ALT2 may promote RPLPS progression. Citation Format: Fernanda Costas C. de Faria, Safiya Khurshid, Patricia Sarchet, Sayumi Tahara, Lucia Casadei, Valerie Grignol, Roma Karna, Sydney Rentsch, Nippin Sp, Joal D Beane, Luciano Mazzoccoli, Matias Montes, Giovanni Nigita, Joe T Sharick, Jennifer L Leigth, Federica Calore, Dawn Chandler, Raphael E Pollock. Oncogenic functions of alternatively spliced MDM2-ALT2 isoform in retroperitoneal liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A054.