Abstract P08: ESTABLISHMENT AND CHARACTERISATION OF LIPOSARCOMA-DERIVED CELLS AS RELEVANT PRE-CLINICAL MODELS FOR TARGET DISCOVERY

Abstract Background: Pre-clinical models that encompass disease heterogeneity are limited for liposarcoma research. We aim to establish and characterise matched liposarcoma-derived tumours and liposarcoma cells cultured in vitro. More importantly, we aim to identify drug susceptibilities in these established liposarcoma (LPS) cells for applications in functional precision medicine. Methods: Liposarcoma tumours and the corresponding patient-derived sarcoma cells (PDSC) established in vitro were profiled using single-cell RNA sequencing (scRNA-seq) at passages 0 and 4. Biological characteristics of PDSCs were validated by differentiation assays, immunofluorescence and fluorescence in-situ hybridisation (FISH). Clinical response to standard-of-care drug doxorubicin was compared to doxorubicin IC50 values in PDSCs. High throughput drug screening was carried out on a panel of 3158 FDA-approved drugs and selective cytotoxicity assay testing of top hits was carried out on primary human mesenchymal stem cells and adipose stem cells. Results: We have successfully established LPS PDSCs with a success rate of 80% (25/31) using our optimised growth factor media. scRNAseq analyses reveal an enrichment of adipocyte stem and progenitor cell (ASPC) population in established PDSCs, with significant heterogeneity among subpopulations harbouring MDM2 and CDK4 amplifications. These findings corroborate with recent evidence identifying MDM2-amplified ASPCs as the potential cell-of-origin in liposarcomas, underscoring their relevance as a targetable cell type for therapeutic discovery. Biological validation demonstrates ASPC marker expression CD55 and DPP4, MDM2 amplification, as well as adipogenic and osteogenic differentiation potential of PDSCs. Doxorubicin IC50 values of PDSCs were concordant to clinical response of patients treated with doxorubicin. Functional drug screening and selective cytotoxic profiling identify several therapeutic vulnerabilities, including susceptibility to proteasome inhibitors, epigenetic inhibitors and tyrosine kinase inhibitors. Conclusion: We demonstrate key histological, molecular and functional characteristics of LPS in our PDSC models. The PDSC models represent biologically and clinically relevant tools for therapeutic target discovery, through which we have uncovered several drug targets with potential utility in the treatment of liposarcomas. Citation Format: Nur Nadiah ISMAIL, Camino Ruano San MARTIN, Zheng Xi YAP, Dexter Kai Hao THNG, Benjamin Jieming CHEN, Vivian Yujing LIM, Nur Fazlin Bte Mohamed Noor, Brandon Xuan Ming PHUA, Tse Hui LIM, Xin Xiu SAM, Chin-Ann Johnny ONG, Claramae Shulyn CHIA, Timothy Kwang Yong TAY, Dean HO, Xing Yi WOO, Tan Boon TOH, Valerie Shiwen YANG. ESTABLISHMENT AND CHARACTERISATION OF LIPOSARCOMA-DERIVED CELLS AS RELEVANT PRE-CLINICAL MODELS FOR TARGET DISCOVERY [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P08.