UCLA

Well-differentiated/dedifferentiated liposarcoma (WD/DD LPS) is a common subtype of soft tissuesarcoma in adults. Our understanding of this disease is lacking and treatment options are limited. First, by investigating tumor metabolomics, we identify asparagine (Asn) as a fundamental purpose for mitochondrial respiration in WD/DD LPS. Asn promotes mTORC1 activity to support tumor growth. Depleting Asn by combining mitochondrial complex I inhibition with asparaginase holds therapeutic potential. Next, we characterize WD/DD LPS beyond histological classification by defining mechanisms of dysregulation in mitochondrial dynamics. WD LPS displays low MAPK signaling activity, elongated mitochondrial morphology, and high mitochondrial respiration. Whereas DD LPS displays high activation of MAPK signaling, which promotes activation of DRP1, fragmentation of mitochondria and a glycolytic phenotype. This shift in mitochondrial bioenergetics promotes tumor growth. Trametinib represents a novel therapeutic approach to target this adaptation. Moreover, Trametinib synergizes with chemotherapy, including agents Pazopanib and Palbociclib, further expanding its clinical potential. DRP1 expression may also serve as a prognostic biomarker, associating with worse survival. Altogether, these findings reveal several adaptations in mitochondrial bioenergetics that provide opportunities for targeted therapy in patients with WD/DD LPS.