Characterizing and targeting the Ewing sarcoma microenvironment to overcome resistance to therapy

Pediatric oncology has pioneered key concepts of cancer therapy: aggressive chemotherapy, international standardization, inclusive clinical trials, and minimal residual disease monitoring. However, few targeted therapies are available for childhood cancers, and low mutation rates limit the number of suitable drug targets and the impact of immunotherapies. Innovative approaches are needed when conducting translational research, most notably for Ewing sarcoma, which has seen stagnating rates of patient survival.

This project pursued the concept that targeted reprogramming of the Ewing sarcoma microenvironment (either of Ewing sarcoma cancer cells or of non-cancer cells within the tumor tissue such as immune cells) may help break chemotherapy resistance and thereby improve treatment response and survival.

We used state-of-the-art technologies (single cell and spatial transcriptomics, single cell epigenomics) to establish a comprehensive map of the Ewing sarcoma microenvironment. We identified epigenetic and transcription-regulatory processes that correspond to Ewing sarcoma tumor cells and non-cancer cells of the Ewing sarcoma tumor microenvironment. We have described the composition of the tumor microenvironment in Ewing sarcoma and revealed the frequently co-localized cell subsets and infer their interaction potential elucidating potential mechanisms of immunosuppressive phenotypes.

Our in-depth analysis of Ewing sarcoma tumor tissues, provides a catalogue of the precise cellular identities and compositions of Ewing sarcoma tumor microenvironment and uncovers alterations in gene regulation that affect their cellular interplay, thus helping to understand the underlying biology of the developmental progression of fusion driven pediatric sarcomas.