(P 53) ESTABLISHMENT AND CHARACTERISATION OF LIPOSARCOMA-DERIVED CELLS AS RELEVANT PRE-CLINICAL MODELS FOR TARGET DISCOVERY

Objective: 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. Subsequently, we aim to identify drug susceptibilities in these established liposarcoma (LPS) cells for target discovery.

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 and subsequently integrated with existing liposarcoma tumour dataset by Gruel et al. Findings were validated by whole genome sequencing, differentiation assays, immunofluorescence and fluorescence in-situ hybridisation (FISH). High throughput drug screening on established PDSCs 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% 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. Functional drug screening and selective cytotoxic profiling identify several therapeutic vulnerabilities, including susceptibility to proteasome inhibitors, epigenetic inhibitors and tyrosine kinase inhibitors.

Conclusion: We have identified, characterised and validated the ASPC population in our liposarcoma PDSC models. Our established models represent biologically relevant pre-clinical platforms for therapeutic target discovery, through which we have uncovered several candidate drug targets with potential utility in the treatment of liposarcomas.