Tumor cell identity and plasticity

Neuroblastoma

I Janoueix-Lerosey, G Schleiermacher and O Delattre

Background: A study of tumor heterogeneity revealed that most neuroblastomas are made up of cells with a noradrenergic precursor phenotype. However, a minority of cells present a completely different epigenetic profile associated with a neural crest type identity. These two cell types co-exist within tumors in variable proportions. Preliminary data from the team suggest that tumor cells have the capacity to shift from one identity to the other.

Hypothesis: Target only one of these two cell types could be insufficient to treat the disease.

Objective: Study cell plasticity in neuroblastoma:

1. Modulate the expression of key cell actors in the regulatory circuits of genes involved in these identity changes and observe the impact of these modulations on the cell phenotype.
2. Study cell heterogeneity in tumors with identity-specific biomarkers.
3. Evaluate the impact of treatment of each individual cell type

Find out more about cell plasticity in neuroblastoma (in French)

Ewing sarcoma

D Surdez and O Delattre

Franzetti et al, Oncogene, 2017 (CC BY-NC-ND 4.0)

Background: Ewing sarcoma is generally characterized by a fusion between the EWS1 and FLI1 genes. This gene fusion leads to the formation of a chimeric protein EWS1-FLI. This chimeric protein acts on the genome in different places. The team has recently demonstrated that the variation of the EWS-FLI1 protein expression level had a considerable impact on the features of Ewing cells. EWS-FLI1^low: the cells have a mesenchymal stem cell phenotype and can migrate while the EWS-FLI1^high proliferate. The shift between these two states is completely reversible.

Hypothesis: A better understanding of the transition mechanism between these two states could have repercussions on therapeutic management.

Objective: Study cell mechanisms responsible for the variations in the EWS-FLI1 level from one cell to another. We will focus on the impact of treatments on the level of EWS-FLI1 and on the impact of STAG2 mutations on cell plasticity.

Image: Franzetti / Laud et al, Oncogene, 2017.

Retinoblastoma

F Radvanyi

Background: Retinoblastoma is a disease made up of two sub-types: the first tumor sub-type expresses cone cell markers, the second sub-type presents an intra-tumor heterogeneity expressing, often exclusively, markers of different cell types in the retina suggesting a multi-cell origin for these tumors.

Hypothesis: tumor heterogeneity and plasticity could be responsible for treatment resistance

Objective: Obtain a better characterization of inter and intra-tumor heterogeneity and better understand plasticity