Heparin CX-01 promotes adipogenesis and counteracts liposarcoma dedifferentiation

ABSTRACT: Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal malignancy sharing driver oncogenes with the low-grade well differentiated liposarcoma. DDLPS, which includes a well differentiated component in most cases, has limited therapeutic options in advanced stages. Exploiting tumor cell plasticity to promote differentiation represents an attractive approach to counteract DDLPS aggressiveness. Heparan sulfate (HS) proteoglycans support pathways implicated in liposarcoma growth and dedifferentiation such as growth factor-mediated and epigenetic regulatory signaling. We used the HS mimetic non-anticoagulant heparin derivative CX-01 (dociparstat) to investigate the effect of HS competition on deregulated adipogenic differentiation and growth of DDLPS models. The antitumor activity of CX-01 was assessed in DDLPS cell lines and patient-derived xenografts (PDXs). In vitro, reactivation of adipogenic program, cell phenotypic changes and accumulation of neutral lipids induced by CX-01 were determined through biochemical analyses, immunofluorescent microscopy and cytofluorimetric/colorimetric methods, The antiadipogenic and growth-promoting activities of pathways targeted by CX-01 were validated through pharmacological/molecular approaches. RNA-Seq transcriptomic analysis was performed on control and CX-01-treated PDX samples. Selected differentially expressed genes (DEGs) were further analyzed in two independent clinical DDLPS databases. CX-01 reduced the proliferative and invasive abilities of DDLPS cell lines inducing cytoskeleton remodeling, lipid accumulation and adipocytic markers. Mechanistic insights demonstrated that CX-01 targets, such as receptor tyrosine kinase-AKT pathways involving c-Met and FGFR, the HS proteoglycan syndecan 1 (SDC1) and heparanase, promoted DDLPS cell growth and impaired differentiation. CX-01 treatment of mice harboring DDLPS PDXs delayed tumor growth and modified the transcriptome affecting pathways associated with the tumor dedifferentiated phenotype (adipogenesis, fatty acid metabolism) and tumor-microenvironment interaction (TGFβ signaling, inflammatory response). SDC1 and other DEGs, including TIMP1, FN1, COL5A1, and MMP14, downmodulated after treatment with CX-01, were found preeminently expressed in the dedifferentiated compared to the well-differentiated tumor component in two independent cohorts of patients with primary DDLPS. These findings demonstrated the potential of the approach based on HS competition to simultaneously inhibit multiple anti-adipogenic players, which singly represent actionable vulnerabilities, and modify the DDLPS transcriptomic profile promoting a more differentiated phenotype compatible with a less aggressive behavior.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307802 | GEO | 2026/09/09

REPOSITORIES: GEO