Abstract 2245: The transcriptomic profile of retroperitoneal primary well differentiated liposarcoma (WDLPS) and well differentiated (WD)/dedifferentiated (DD) components of DD liposarcoma (DDLPS) reveals the progression from WDLPS to DDLPS
Authors: Pasquali Sandro , Percio Stefano , Callegaro Dario , Martini Silvia , Beretta Alessia , Bertolotti Alessia , Brich Silvia , Collini Paola , Barisella Marta , De Cecco Loris , Vallacchi Viviana , Stacchiotti Silvia , Benelli Matteo , Gronchi Alessandro , Zaffaroni Nadia 
Published: April 2023

Abstract
This study aimed at unravelling whether WDLPS undergo a progressive evolution to DDLPS through analyzing the transcriptomic profile of retroperitoneal liposarcoma. In a contemporary retrospective series of primary retroperitoneal DDLPS and WDLPS (N=107), we sampled paired DD/WD/normal fat (NF) components of DDLPS and paired WD/NF components of WDLPS. RNA-Seq data was normalized using the trimmed mean of M-value (TMM) algorithm, heteroscedasticity was removed, and differential expression analysis (DEA) performed. Gene sets enrichment analysis (GSEA) evaluated enrichment in biological hallmarks and was performed to overcome FDR correction of DEA and evaluate the ensemble. FDR threshold 0.05 was considered for significance. Marked transcriptional changes exist among paired components of DDLPS (DD, WD, NF) or WDLPS (WD, NF). Although DEA did not show significant changes between WD and NF components of DDLPS and WDLPS, GSEA analysis highlighted deregulation in hallmarks. An upregulation of G2M checkpoint and mitotic spindle gene sets was observed when WD components of DDLPS was compared to WDLPS and progressively increase in the DD component. Some targetable genes from the leading edge of these pathways (PLK1, AURKA, and EZH2) as well as the primary oncogenic drivers (MDM2, CDK4, and HMGA2) of liposarcoma were functionally validated with targeted agents in cell lines of DDLPS and WDLPS, supporting findings of transcriptomic analysis. We also observed that adipogenesis, fatty acid metabolism, cholesterol homeostasis, oxidative phosphorylation, and peroxisome gene sets were down-regulated in the DD component, while glycolysis was upregulated compared to WD components. When NF were compared with their paired tumor components, G2M checkpoint and mitotic spindle gene sets did not differ between DDLPS and WDLPS, suggesting these two hallmarks as tumor-specific. NF of patients with DDLPS demonstrated higher expression of adipogenesis, and other pathways related to metabolism suggesting its metabolic activation compared to NF of patients with WDLPS. In conclusion, changes distinguishing WDLPS/DDLPS early at the WD stage and progressively increasing in the DD component of DDLPS supported the hypothesis of an orderly progression from WDLPS to DDLPS and represent a source of additional therapeutic targets.
Citation Format: Sandro Pasquali, Stefano Percio, Dario Callegaro, Silvia Martini, Alessia Beretta, Alessia Bertolotti, Silvia Brich, Paola Collini, Marta Barisella, Loris De Cecco, Viviana Vallacchi, Silvia Stacchiotti, Matteo Benelli, Alessandro Gronchi, Nadia Zaffaroni. The transcriptomic profile of retroperitoneal primary well differentiated liposarcoma (WDLPS) and well differentiated (WD)/dedifferentiated (DD) components of DD liposarcoma (DDLPS) reveals the progression from WDLPS to DDLPS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2245.