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Abstract Dedifferentiated liposarcoma (DDLPS) is a rare, life-threatening malignancy in the family of adipocytic sarcomas. DDLPS, which usually arises in the retroperitoneum of middle-aged adults, has a poor prognosis. This is due to the propensity of DDLPS to metastasize and recur locally, combined with a dearth of effective systemic therapies. A longstanding curiosity is that DDLPS has non-lipogenic morphology and no lipid droplets, while its less aggressive sister sarcoma, well-differentiated liposarcoma (WDLPS), resembles benign adipose tissue and contains large lipid droplets. How DDLPS metabolizes lipids and the metabolic vulnerabilities of DDLPS in patients, which may form new therapeutic targets, are unknown. In our project, we investigate the metabolism of DDLPS versus WDLPS using patient samples and cell lines. Snap-frozen tissues from patients were obtained from the Dana-Farber/Harvard Cancer Center specimen bank of DDLPS and WDLPS. We performed metabolomics and lipidomics on these samples. We complemented these results with publicly available transcriptional profiles of separate cohorts of DDLPS, WDLPS, and other cancers. In vitro, we made use of a panel of multiple DDLPS-derived cell lines, WDLPS-derived cells, benign preadipocytes, and benign adipocytes. We measured mitochondrial function and the cellular effects of perturbing various metabolites in screens in culture. Overall, our initial results indicate strong alterations in mitochondrial metabolism in DDLPS in patients. In culture, DDLPS is susceptible to multiple metabolic perturbations related to mitochondrial dysfunction. These metabolic vulnerabilities of DDLPS provide potential therapeutic opportunities. Work is ongoing to optimize the targeting of these vulnerabilities in vivo, elucidate the molecular roles of specific metabolites, and complete a blueprint of DDLPS metabolic weaknesses in patients. Citation Format: Jamie O. Brett, Ji Seul Han, Choah Kim, Liam P. Kelley, SeongJun Han, Dylan Boone, Joseph Crowley, Shakchhi Joshi, Chandrajit P. Raut, Anna Greka, Marcia C. Haigis. Metabolic vulnerabilities of dedifferentiated liposarcoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4425.
Brett et al. (Fri,) studied this question.