Deciphering context-dependent roles of oncogenic gene fusions in vivo

Sarcomas are an extremely heterogeneous group of mesenchymal cancers, many of which remain lethal despite decades of clinical trials. A unifying characteristic in pediatric sarcomas is their low mutational burden.

Instead, they frequently harbor an entity-specific chromosomal rearrangement giving rise to an oncofusion protein that acts as the disease driver.

This genetic simplicity underlying a complex group of tumors implies a synergy between oncofusions and the cellular context in which they occur. However, the cell-of-origin for the vast majority of sarcomas is unknown.

We have developed a flexible method for somatic engineering of the mouse muscle to model more than 10 genetically distinct pediatric sarcoma subtypes.

Here we will take advantage of this unique tool to understand key questions so far unanswered due to the lack of suitable sarcoma models and flexible genetic approaches:1.What is the identity of the cell(s) of origin and why are they permissive to transformation? 2.Are gene fusions required for tumor maintenance?

And if they are, to what extent is transformation reversible? Do tumor cells retain memory of their previous normal states? Or there is a point of no return when they forget what they used to be?

By combining our models with transgenic mouse lines that allow in vivo cell barcoding, we will trace, isolate and characterize different population of cells in normal muscle and in primary tumors to identify and study sarcoma cells-of-origin.

To understand the role of gene fusions in tumor maintenance we will apply the degradation system (dTAG) for in vivo acute degradation of oncofusion proteins. Temporal and spatial analysis will allow to dissect complex biological responses to oncogene withdrawal.

These approaches will combine cutting-edge technologies to provide fundamental knowledge on the mechanisms underlying tumorigenesis, their intertwining with existing cellular states and the potential of oncofusion withdrawal for sarcoma treatment.