Periodic Reporting for period 1 - SARCOMAkids (Developmentally programmed pediatric sarcomas: a versatile platform for drug discovery and molecular precision medicine)
Période du rapport: 2023-10-01 au 2026-03-31
Paediatric bone and soft tissue tumours, such as Ewing sarcomas, represent a significant clinical challenge. Although these cancers account for approximately 20% of childhood malignancies, survival rates have remained largely unchanged over the past four decades. Current treatment protocols are limited, and progress has been hampered by a fundamental lack of understanding of the underlying biology of these tumours. Traditional cell lines fail to fully capture the complexity of Ewing sarcoma, and even advanced patient-derived xenograft models or organoids often lose crucial information about tumour development. As a result, promising therapeutic ideas cannot be reliably tested, creating a critical bottleneck in the development of new treatments.
The SARCOMAkids project addresses this urgent need through a “build it to understand it” approach. Instead of relying on conventional trial-and-error methods, the project aims to systematically construct biologically faithful models of Ewing sarcoma from human pluripotent stem cells. By differentiating these stem cells into multiple developmental stages and inducing the expression of the characteristic EWSR1::FLI1 fusion protein, researchers can recreate the earliest events of tumour formation. This approach allows the identification of the cell states permissive to oncogenic transformation and the reconstruction of the supportive tumour microenvironment, providing a comprehensive framework for studying disease mechanisms.
The overarching objectives of the project are:
1. To generate accurate cellular models of Ewing sarcoma that reflect the developmental origins and molecular characteristics of the tumour.
2. To map oncogene-competent cell states and define the conditions required for tumour initiation.
3. To recreate and study the tumour microenvironment in vitro and in vivo, enabling biologically meaningful experiments that inform drug testing.
Through these efforts, SARCOMAkids is expected to provide a transformative platform for drug discovery and precision medicine in paediatric sarcomas. By creating models that faithfully recapitulate tumour biology, the project aims to overcome a major obstacle in the field, potentially accelerating the development of new therapies for children with these devastating cancers. The significance of this work extends beyond Ewing sarcoma, offering a blueprint for modelling other paediatric cancers driven by fusion oncogenes.
The SARCOMAkids project addresses this urgent need through a “build it to understand it” approach. Instead of relying on conventional trial-and-error methods, the project aims to systematically construct biologically faithful models of Ewing sarcoma from human pluripotent stem cells. By differentiating these stem cells into multiple developmental stages and inducing the expression of the characteristic EWSR1::FLI1 fusion protein, researchers can recreate the earliest events of tumour formation. This approach allows the identification of the cell states permissive to oncogenic transformation and the reconstruction of the supportive tumour microenvironment, providing a comprehensive framework for studying disease mechanisms.
The overarching objectives of the project are:
1. To generate accurate cellular models of Ewing sarcoma that reflect the developmental origins and molecular characteristics of the tumour.
2. To map oncogene-competent cell states and define the conditions required for tumour initiation.
3. To recreate and study the tumour microenvironment in vitro and in vivo, enabling biologically meaningful experiments that inform drug testing.
Through these efforts, SARCOMAkids is expected to provide a transformative platform for drug discovery and precision medicine in paediatric sarcomas. By creating models that faithfully recapitulate tumour biology, the project aims to overcome a major obstacle in the field, potentially accelerating the development of new therapies for children with these devastating cancers. The significance of this work extends beyond Ewing sarcoma, offering a blueprint for modelling other paediatric cancers driven by fusion oncogenes.
During the first two years of the SARCOMAkids project, we have developed a set of methodological frameworks that enable systematic investigation of the cell(s)-of-origin and early transformation events in Ewing sarcoma. These tools and approaches will be made available to the research community at subsequent stages of the project.
More specifically we have:
Established a suite of inducible human pluripotent stem cell (hPSC) models engineered to express Ewing sarcoma fusion oncogenes (EWSR1::FLI1 and EWSR1::ERG) in a temporally controlled manner.
Defined a ‘simple recipe’ for making Ewing-sarcoma like tumours and programming cells in permissible states of fusion oncogene expression.
Established an in vitro 3D platform for building Ewing sarcoma-like models including cells of the tumour microenvironment.
Established teratomas as an in vivo source for potential cell(s)-of- origin for Ewing sarcoma.
More specifically we have:
Established a suite of inducible human pluripotent stem cell (hPSC) models engineered to express Ewing sarcoma fusion oncogenes (EWSR1::FLI1 and EWSR1::ERG) in a temporally controlled manner.
Defined a ‘simple recipe’ for making Ewing-sarcoma like tumours and programming cells in permissible states of fusion oncogene expression.
Established an in vitro 3D platform for building Ewing sarcoma-like models including cells of the tumour microenvironment.
Established teratomas as an in vivo source for potential cell(s)-of- origin for Ewing sarcoma.
Our achievement during the first reporting period represents significant breakthroughs and advance the field well beyond the current state-of-the-art. Most notably, we have generated de novo human models resembling Ewing sarcoma tumours, created by engineering human pluripotent stem cells and organoid systems to undergo fusion-oncogene-driven transformation. This constitutes a major advance because it simultaneously enables systematic dissection of the molecular and cellular mechanisms underlying Ewing sarcoma initiation, and the establishment of new experimental platforms for future therapeutic discovery.