Abstract 1180: Epigenetic dysregulation of IGF1 and PPARG2 in dedifferentiated liposarcoma

Abstract Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) is among the most common types of adult sarcoma and holds valuable insights into dysfunctional differentiation given its well- and de-differentiated histologic subtypes (WDLPS and DDLPS, respectively). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood, limiting the therapeutic options for DDLPS to empiric cytotoxic chemotherapies. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human normal adipose, WDLPS, and DDLPS tissue samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) signaling and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 signaling loss was exclusive to the DDLPS component within mixed histology tumors and IGF1 loss was associated with worse overall survival in LPS patients. In normal adipocytes, IGF1 signals upstream of peroxisome proliferator-activated receptor gamma (PPARG) to induce lineage-specific terminal differentiation. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS cells led to a block in differentiation that could not be overcome with the addition of either exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease. Citation Format: Erica Maria Pimenta, Amanda E. Garza, Sabrina Y. Camp, Jihye Park, Samantha E. Hoffman, Laura Valderrabano, Jingxin Fu, Kevin Bi, Julie Karam, Breanna M. Titchen, Melin K. Khandekar, Erin Shannon, Yun Jee Kang, Anwesha Nag, Aaron R. Thorner, Chandrajit R. Raut, Jason L. Hornick, Priscilla Merriam, Nicole L. Solimini, Suzanne George, George D. Demetri, Eliezer M. Van Allen. Epigenetic dysregulation of IGF1 and PPARG2 in dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1180.