Transcriptional Heterogeneity in Dedifferentiated Liposarcoma Reveals Distinct Cell-Cycle Subtypes

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Dedifferentiated liposarcoma (DDLPS) is characterized by cyclin-dependent kinase 4 (CDK4) amplification.
• Responses to CDK4/6 inhibitors in DDLPS are heterogeneous.
• Transcriptional heterogeneity in cell-cycle regulators may define DDLPS subtypes and influence inhibitor sensitivity.

Purpose of the Study:

• To determine if transcriptional heterogeneity in cell-cycle regulators defines distinct DDLPS subtypes.
• To investigate if these subtypes correlate with CDK4/6 inhibitor sensitivity.

Main Methods:

• Analyzed RNA sequencing data from 57 DDLPS tumors in The Cancer Genome Atlas (TCGA-SARC) cohort.
• Evaluated cell-cycle regulator expression relative to CDK4 expression.
• Performed unsupervised clustering to identify transcriptional subgroups and assess pathway activity.

Main Results:

• Identified three transcriptionally distinct DDLPS subgroups based on CDK4 and CDK2 expression patterns.
• Observed divergent pathway activity profiles across subgroups.
• One subgroup showed high CDK4/low CDK2 with inflammatory signaling; another showed high CDK4/CDK2 with proliferative signaling; a third showed low CDK4/CDK2 with hormone signaling.

Conclusions:

• DDLPS tumors exhibit distinct transcriptional states within the CDK4-RB network.
• These states may influence tumor dependence on CDK4 signaling.
• This heterogeneity likely contributes to variable sensitivity to CDK4/6 inhibitors and clinical outcomes.