Developmentally programmed pediatric sarcomas: a versatile platform for drug discovery and molecular precision medicine

Introduction

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.

Focus on Ewing Sarcoma

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).

Model Validation

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, including:

1. Targeting the regulatory programs of Ewing sarcoma cells
2. Investigating metabolic dependencies of the tumor microenvironment
3. Studying developmentally programmed tumors in their in vivo context

Building Ewing Sarcoma Models

To build Ewing sarcoma models in a molecularly defined manner, we will:

1. Map oncogene-competent cell states by inducing EWS-FLI1 expression in hPSC-based models of human development (Aim 1).
2. Create supportive tumor microenvironments by 3D differentiation and CRISPR screening in stromal cells (Aim 2).
3. Evaluate the ability of in vitro models to form tumors in mice, and pursue full in vivo modeling of Ewing sarcoma using genetically engineered teratomas (Aim 3).

Comparison with Existing Models

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.

Generalization to Other Tumor Types

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.