Project description
Mapping to transform paediatric sarcoma research
Paediatric sarcomas represent approximately 20 % of childhood cancers. Despite medical advancements, their survival rates have remained stagnant for the past three decades. This underscores the need for novel approaches in understanding and treating these devastating tumours. With this in mind, the ERC-funded SARCOMAkids project will develop a new approach. Specifically, it will focus on Ewing sarcoma, a developmental cancer driven by fusion oncogenes. The project will construct innovative cellular models from human pluripotent stem cells. By mimicking the developmental origins of these tumours, researchers hope to accelerate drug discovery and precision medicine. Through mapping of oncogene-competent cell states and crafting supportive tumour microenvironments, SARCOMAkids promises to revolutionise our understanding of paediatric sarcomas.
Objective
Pediatric sarcomas account for ~20% of childhood cancers. They have disappointing survival rates, with very little therapeutic progress over the last three decades. We clearly have to rethink the science and find new ways to tackle these devastating tumors. I propose that new cellular models are needed that account for the developmental origins of pediatric sarcoma, in order to accelerate drug discovery and molecular precision medicine.
Focusing on Ewing sarcoma, which is a developmental cancer caused by a (known) fusion oncogene expressed in (unknown) cells-of-origin, we will pursue a “build it to understand it” approach and construct in vitro and in vivo tumor models starting from human pluripotent stem cells (hPSCs). We will validate these models against our single-cell and spatial maps of Ewing sarcoma tumors, and we will pursue initial applications in academic drug discovery – targeting the regulatory programs of Ewing sarcoma cells, metabolic dependencies of the tumor microenvironment and developmentally programmed tumors in their in vivo context.
To build Ewing sarcoma models in a molecular defined manner, we will map oncogene-competent cell states by inducing EWS-FLI1 expression in hPSC-based models of human development (Aim 1). We will create supportive tumor microenvironments by 3D differentiation and CRISPR screening in stromal cells (Aim 2). Finally, we will evaluate the ability of in vitro models to form tumors in mice, and we will pursue full in vivo modeling of Ewing sarcoma using genetically engineered teratomas (Aim 3).
Compared to patient-derived xenografts, organoids or cell lines, our approach captures early events of tumorigenesis, providing complementary in vitro and in vivo models of Ewing sarcoma for biomedical and translational research. This approach will generalize to other tumor types, as it takes the concept of developmental cancers seriously and operationalizes it using cellular programming and high-throughput functional biology.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
1090 Wien
Austria