Dr Pimenta on Adipogenesis Defects Characteristic of Dedifferentiated Liposarcoma

“The key finding here is that [during adipogenesis], dedifferentiated liposarcoma cells [can] lose a lineage-specific protein that’s necessary for differentiation.”

Erica Maria Pimenta, MD, PhD, a postdoctoral research fellow at Dana-Farber Cancer Institute and a clinical fellow in medicine at Brigham and Women’s Hospital, discussed findings from a study investigating epigenetic dysregulation of the IGF1/PPARG2 signaling pathway in dedifferentiated liposarcoma.

This study used single-nucleus multiome sequencing and spatial profiling to characterize defects in adipocyte-specific differentiation within human well-differentiated liposarcoma cells, dedifferentiated liposarcoma cells, and normal human adipose.

Investigators found that insulin-mediated adipogenesis through IGF1 signaling was present in well-differentiated liposarcoma, but not in dedifferentiated liposarcoma, Pimenta said. Notably, this loss of IGF1 was associated with worse overall survival outcomes in patients with liposarcoma.

Additionally, gain of cellular programs related to early mesenchymal development and GLP-1–induced insulin secretion was also found to be a hallmark of dedifferentiated liposarcoma. Epigenomic analysis revealed similar findings, she noted.

Furthermore, this study indicated that GLP-1 signaling may regulate dedifferentiated disease, she explained. Spatial transcriptomics profiling validated this finding, she stated. In normal adipocytes, IGF1 signals upstream of PPARG and indices lineage-specific differentiation. Based on this knowledge, the investigators evaluated whether IDF1 exposure could cause liposarcoma cells to differentiate, Pimenta reported. However, in vitro stimulation of the IFG1 signaling pathway showed a deficiency in the PPARG isoform PPARG2, which prevents PPARG1 from binding to its transcription start site, according to Pimenta.

IGF1/PPARG2 signaling is accordingly disrupted, and dedifferentiated liposarcoma cells are unable to respond to differentiation signals in the TME, she explained. These barriers were not able to be reversed with the addition of exogenous IGF1 or pro-adipogenic PPARG and GLP-1 agonists, she added. Overall, this study showed that dedifferentiated liposarcoma cells can develop lineage-specificdefects during adipogenesis that result in the loss of necessary components for proper differentiation, she concluded.