Related Experiment Video
Updated: Dec 28, 2025
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution
Marie-Ming Aynaud1, Olivier Mirabeau1, Nadege Gruel2
1INSERM U830, Équipe Labellisée LNCC, SIREDO Oncology Centre, Institut Curie, 75005 Paris, France.
Abstract:
EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive the heterogeneity of transcriptional programs. Here, we combine independent component analysis of single-cell RNA sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus define an exquisitely specific and direct enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation and strong oxidative phosphorylation metabolism are associated with a well-defined range of EWSR1-FLI1 activity. In contrast, a subpopulation of cells from below and above the intermediary EWSR1-FLI1 activity is characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within EwS tumors.
Insights
Ewing sarcoma (EwS) cells show varied gene activity despite genetic similarity. This study maps the EWSR1-FLI1 oncogene
Area of Science:
- Cancer Biology
- Molecular Oncology
- Genomics
Background:
- Ewing sarcoma (EwS) is driven by the EWSR1-FLI1 oncogene, which causes cell transformation.
- The mechanisms by which genetically uniform EwS cells generate diverse transcriptional programs remain unclear.
- Understanding this heterogeneity is crucial for developing targeted therapies.
Purpose of the Study:
- To characterize dynamic cellular processes linked to EWSR1-FLI1 activity.
- To define the specific enhancer-driven EWSR1-FLI1 program.
- To identify sources of intratumoral heterogeneity in EwS.
Main Methods:
- Integration of independent component analysis on single-cell RNA sequencing data.
- Time-resolved mapping of EWSR1-FLI1 binding sites.
- Analysis of open chromatin regions across diverse cell types and model systems.
Main Results:
- A specific, direct enhancer-driven EWSR1-FLI1 program was defined.
- In EwS tumors, high cell proliferation and oxidative phosphorylation correlate with a defined EWSR1-FLI1 activity range.
- A subpopulation of cells with altered EWSR1-FLI1 activity exhibits increased hypoxia.
Conclusions:
- EWSR1-FLI1 activity directly influences distinct cellular states within EwS tumors.
- Heterogeneity in EwS is partly driven by variations in EWSR1-FLI1 activity and associated metabolic states.
- These findings provide insights into the molecular basis of EwS intratumoral heterogeneity.
