Mechanistic insights into liposarcoma progression.

Ellen Kendall

Document Type

Article

Publication Date

Summer 2017

JAX Location

In: Student Reports, Summer 2017, Jackson Laboratory

Abstract

Liposarcoma is a rare malignant tumor of fat cells. The molecular events leading to the development of the tumor are poorly understood, and biomarkers and curative treatments are not available at developed stages. A recent study generated mice with adipose tissue deficiency of two enzymes used in lipolysis, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). In experimentation, all double adipose knockout (DKO) mice developed liposarcoma, resembling the pathology of human dedifferentiated liposarcoma. Microarray expression data was analyzed for wild type (WT) mice, mice with each sing le knockout, and double knockout mice at three, seven, and twelve months. DKO mice were found to have a distinct transcriptional profile by three months, leading to unique enriched metabolic pathways. WT mice had a metabolic expression profile related to fatty acid oxidation, while DKO mice had a metabolic expression profile related to glycolysis. Transcription factors upstream of the enriched metabolic pathways in DKO mice were used to construct a gene regulatory network model. Theoretical gene states of the regulatory network were predicted using Random Circuit Perturbation (RACIPE), and were confirmed with experimentally observed expression levels in WT and DKO mice. Gene circuit regulation modeling with RACIPE identified E2f1 and Mdm2 as key transcription factors that helped define a DKO specific transition state in liposarcoma progression. Findings from RACIPE mirrored that of experimentally observed expression data, wherein E2f1 and Mdm2 were identified as key transcription factors promoting liposarcoma development in DKO mice, making them promising candidates for liposarcoma biomarkers and therapeutic targets in the future.

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