Abstract Human liposarcoma (LPS) is a deadly and the most common soft tissue cancer whose cellular origin and molecular regulation are unclear. Using a novel transgenic mouse model, we made a seminal discovery in our unpublished preliminary results that aberrant activation Notch signaling in mature adipocytes drives their dedifferentiation and formation of LPS. Notch signaling is an evolutionarily conserved signal transduction cascade that plays an important role in development, cell-cell communication and stem cell differentiation. Aberrant Notch activity has been implicated in several types of cancers including leukemia, breast cancer and osteosarcoma but its role in LPS has not been reported. While our series of preliminary studies have established the adipocyte origin and pathogenic process of LPS in the mouse model, several imperative questions stood out to be addressed in the proposed work. First, we will distinguish the relative role of Notch activity and metabolic dysfunction – an accompanying feature of the LPS transgenic mouse model – in the development and pathogenesis of LPS. Second, we will investigate the role of Notch signaling in human liposarcomas. Third, we will dissect and molecular mechanisms underlying Notch-driven LPS based on our preliminary genomics and lipidomics results, and futher explore therapeutic interventions to treat the murine and human LPS in xenograft mouse models. Results from the proposed work will for the first time uncover the oncogenic function of Notch signaling in adipocytes and adipose tissue, one of the most important metabolic organs in the body. In addition, our transgenic mouse model will represent a unique tool to study the etiology, pathogenesis and treatment of human LPS.