Simple SummaryLiposarcomas (LPSs) are a rare soft tissue malignancy with a variable clinical prognosis dependent on tumor differentiation. Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas most commonly occur both in extremities and the retroperitoneal cavity. Surgical resection and post-operative monitoring are effective forms of treatment; however, many tumors do recur and require chemotherapeutic intervention. Liposarcomas have high intratumoral variability, which can influence drug response and microenvironment interactions. Using a broad bioinformatics approach, we show that Hedgehog signaling, a developmental pathway, is upregulated in DDLPS and correlates with a tumor gene expression signature that suggests reduced immune cell infiltration and increased extracellular matrix (ECM) protein expression.AbstractLiposarcomas are the most diagnosed soft tissue sarcoma, with most cases consisting of well-differentiated (WDLPS) or dedifferentiated (DDLPS) histological subtypes. While both tumor subtypes can have clinical recurrence due to incomplete resections, DDLPS often has worse prognosis due to a higher likelihood of metastasis compared to its well-differentiated counterpart. Unfortunately, targeted therapeutic interventions have lagged in sarcoma oncology, making the need for molecular targeted therapies a promising future area of research for this family of malignancies. In this work, previously published data were analyzed to identify differential pathways that may contribute to the dedifferentiation process in liposarcoma. Interestingly, Gli-mediated Hedgehog signaling appeared to be enriched in dedifferentiated adipose progenitor cells and DDLPS tumors, and coincidentally Gli1 is often co-amplified with MDM2 and CDK4, given its genomic proximity along chromosome 12q13-12q15. However, we find that Gli2, but not Gli1, is differentially expressed between WDLPS and DDLPS, with a noticeable co-expression signature between Gli2 and genes involved in ECM remodeling. Additionally, Gli2 co-expression had a noticeable transcriptional signature that could suggest Gli-mediated Hedgehog signaling as an associated pathway contributing to poor immune infiltration in these tumors.