Profiling site-specific cell states of Ewing Sarcoma xenografts in zebrafish
A key challenge in cancer research is to identify functional cell states as they relate to specific tissue microenvironments. In this work, we present a quantitative high-resolution imaging assay of cancer cell morphology in zebrafish xenografts to probe functional adaptation to variable cell extrinsic cues and molecular interventions. We focus on Ewing Sarcoma, a pediatric cancer driven by a single oncogenic fusion protein EWSR1-FLI1, and with little to no additional somatic mutations, making it a prototypical form of cancer whose adaptation is likely driven by acute, non-genomic mechanisms. By applying machine learning approaches to 3D cell shapes, we find systematic shifts in the distribution of cell morphological states between seeding sites in the fish embryo, as well as between cells with differential expression of EWSR1-FLI1 in an environmentally sensitive fashion. We propose a model where Ewing Sarcoma cancer cell plasticity is sensitive both to expression fluctuation of EWSR1-FLI1 and signals from the surrounding tissue microenvironment, with either or both factors possibly contributing to metastatic potential.