Tracking Ewing Sarcoma Origin by Developmental and Trans-species Genomics
Project Team
Florian Halbritter, PhD, St. Anna Children's Cancer Research Institute, Vienna, Austria
Martin Distel, PhD, St. Anna Children's Cancer Research Institute, Vienna, Austria
Igor Adameyko, PhD, Medical University of Vienna, Vienna, Austria
Matthias Farlik, PhD, Medical University of Vienna, Vienna, Austria
Cornelia Kasper, PhD, University of Natural Resources and Life Sciences, Vienna, Austria
Malignant bone tumors, mainly Ewing sarcoma and osteosarcoma, comprise about 6% of all cancers in children and adolescents. Although more than 60% of patients can be saved with current multi-modal genotoxic treatment regimens, survivors suffer from therapy-induced life-long morbidity emphasizing the urgent need for less toxic, targeted medications for patients. While a large number of such candidate compounds have become available, the rarity of the disease drastically limits conventional drug development strategies and thus access of patients to innovative treatment options. This bottleneck may be overcome if we had laboratory models faithfully recapitulating the human disease for pre-clinical drug testing. The design of such models requires deep knowledge of tumor histogenesis (i.e., of how tumors develop out of normal tissues), which is largely lacking for bone sarcomas. The genetic cause of Ewing sarcoma is a mutation that results in the expression of an oncogenic fusion protein called EWS-FLI1, with disastrous effects on the enigmatic Ewing sarcoma progenitor cell. There is evidence that Ewing sarcoma develops from some kind of mesenchymal stem cells from the bone marrow or the neural crest (as transient structure arising during fetal development). Mesenchymal stem cells are a heterogeneous group of stromal cells that can develop into various tissues including bone, fat, and cartilage. Little is known about the precise dynamics of normal and perturbed differentiation of mesenchymal stem cells, making it difficult to establish a link to bone sarcoma tumorigenesis. In this project, we will follow two complementary approaches to decipher the tissue and stage of origin for Ewing sarcoma and osteosarcoma to facilitate pre-clinical model development.
2023 Update
We aim at elucidating bone sarcoma origin considering cell type and its developmental stage at the time of tumor initiation to better understand disease pathogenesis and to develop urgently needed disease models for pre-clinical drug testing. We have taken the first steps towards establishing a molecular reference atlas of human mesenchymal and neural crest stem cell development to chart different aspects of bone sarcoma pathogenesis. We focus on the disruptive effect of the EWS-FLI1 oncogene and link disrupted differentiation to Ewing sarcoma. A pipeline to resolve normal and perturbed stem cell development on the single-cell level was established. In a pilot experiment, we demonstrated that induction of EWS-FLI1 early during differentiation towards any of four lineages (bone, cartilage, fat, neurons) changes their gene expression programs in a unique way. As tissue development is highly conserved between vertebrate species and the tumor maintains a “memory” of its tissue-of-origin, we explore a zebrafish model to interrogate Ewing sarcoma-specific molecular features for the identification of cell-of-origin candidates. Using epigenomic data of human Ewing sarcoma we identified genomic elements presumed to carry epigenetic memory of the cell type of disease origin. We tested more than 30 such elements in zebrafish and demonstrated convergent activity in specific larval cell types. We also discovered a role for the genetic background of wildtype zebrafish supporting EWS-FLI1-driven tumorigenesis. Eventually, our innovative combinatorial approach will identify equivalent cell types across vertebrate species that serve as bone sarcoma precursors in humans and characterize developmental cell states susceptible to sarcomagenesis.
Project Goal
This project aims at elucidating bone sarcoma origin considering cell type and its developmental stage at the time of tumor initiation. Our long-term objectives are to better understand disease pathogenesis resulting from perturbed cell differentiation, and to develop urgently needed disease models for pre-clinical drug testing. As conventional modelling approaches in mice have so far failed to result in tumors recapitulating the human disease in Ewing sarcoma, we will follow two innovative approaches to overcome our lack of knowledge on bone sarcoma origin. We will establish a molecular reference atlas of human mesenchymal stem cell development and use it to chart different aspects of bone sarcoma pathogenesis. We will focus on the disruptive effect of the EWS-FLI1 oncogene and link disrupted differentiation to Ewing sarcoma. As tissue development is highly conserved between vertebrate species and the tumor maintains a “memory” of its tissue-of-origin, we will explore a zebrafish model to interrogate Ewing sarcoma-specific molecular features for the identification of cell-of-origin candidates. Eventually our innovative combinatorial approach will identify equivalent cell types across vertebrate species that serve as bone sarcoma precursors in humans and characterize developmental cell states susceptible to sarcomagenesis. This will allow applying drugs that nudge the balance of differentiation towards one cell lineage as a new treatment opportunity for bone sarcoma. Beyond the lifetime and scope of this project, the generated dataset will be a highly valuable resource for biomedical research, with broad relevance for pediatric sarcomas and regenerative medicine.
