Periodic Reporting for period 1 - CAtS (Deciphering the developmental roots of childhood sarcoma cells – combining single cell sequencing technologies and machine learning)
Reporting period: 2020-11-09 to 2022-11-08
In Europe, the leading cause of death by disease for children is cancer. For survivors, they live with treatment-related complications for the remainder of their lives highlighting a need for less toxic therapeutic strategies. The CAtS Action, “Cell Atlas of Sarcoma: Deciphering the developmental roots of childhood sarcoma cells” sought to understand how childhood sarcomas develop with the long-term goals of developing new treatment avenues for patients. Sarcomas are cancers of the bone and soft tissue that arise more commonly in children than adults. Sarcomas can develop in almost any part of the body, including the legs, arms and abdomen. Adult cancers arise from the accumulation of mutations over decades each time a cell divides. However, in childhood cancer, the causes of cancer are not understood as clearly.
The overall aim of the action was to create a cell ‘atlas’ of sarcoma to find new treatment targets for paediatric patients. We applied single-cell RNA sequencing, a methodology that profiles individual cancer cells within each sample. These profiles can be used to learn what it means to be a sarcoma and how these cells differ from healthy cells. By creating an atlas of sarcoma, we could identify every component of a tumour, with fine resolution, allowing us to determine the differences between healthy and cancer cells and find potential treatment targets. Upon successful completion of this action, we were able to identify foetal genes that were repurposed by cancer cells. These genes should not exist after birth, yet they persist in tumours and contribute to oncogenic progression. Due to the exclusive nature of these genes in these cancers, they are attractive targets for treatment and offer immense translation applications of the atlases we created.
The specific objectives of the Marie Skłodowska Curie Action (MSCA) have been to (a) collect and sequence childhood sarcomas (bone and muscle cancers); (b) collect and sequence embryonic and foetal normal reference bone and muscle; and (c) develop and apply new computational tools to understand childhood sarcoma. A parallel goal of the MSCA fellowship was to hone the skills and facilitate the career development of the researcher.
The overall aim of the action was to create a cell ‘atlas’ of sarcoma to find new treatment targets for paediatric patients. We applied single-cell RNA sequencing, a methodology that profiles individual cancer cells within each sample. These profiles can be used to learn what it means to be a sarcoma and how these cells differ from healthy cells. By creating an atlas of sarcoma, we could identify every component of a tumour, with fine resolution, allowing us to determine the differences between healthy and cancer cells and find potential treatment targets. Upon successful completion of this action, we were able to identify foetal genes that were repurposed by cancer cells. These genes should not exist after birth, yet they persist in tumours and contribute to oncogenic progression. Due to the exclusive nature of these genes in these cancers, they are attractive targets for treatment and offer immense translation applications of the atlases we created.
The specific objectives of the Marie Skłodowska Curie Action (MSCA) have been to (a) collect and sequence childhood sarcomas (bone and muscle cancers); (b) collect and sequence embryonic and foetal normal reference bone and muscle; and (c) develop and apply new computational tools to understand childhood sarcoma. A parallel goal of the MSCA fellowship was to hone the skills and facilitate the career development of the researcher.
This action was carried out via 3 work packages (WPs). WP1 comprised the collection, isolation and sequencing of single-cells from a childhood bone cancer, called osteosarcoma, and a childhood muscle cancer called rhabdomyosarcoma. We successfully created single-cell atlases of these two cancer types, fully encompassing the full heterogeneity of these diseases. Using these atlases, we were able to pinpoint exactly where foetal bone and muscle development goes awry and a maturation block occurs within these cancers. These atlases will be available for the sarcoma community upon publication this year in the form of raw sequencing data, gene counts data and a user-friendly website. WP2 involved the collection, isolation and sequencing of normal reference material: embryonic and foetal bone and muscle. Parts of these atlases will be published in 2 publications this year (atlas of the human limb bud and foetal spine, both are currently in review). Lastly, WP3 consisted of the development of computational tools and frameworks to characterize sarcoma single cells and map them on developmental trajectories. One of these tools, alleleintegrator, was published in Communications Biology last year, while the other tools will be published with the larger sarcoma paper this year. This includes a computational framework to identify oncofetal targets – genes that are expressed exclusively during the foetal period and should not be expressed in adult tissues, yet persist in cancers. These are formidable targets for immunotherapies.
This MSCA action has been or will be disseminated in a number of ways, beyond academic publication. The preliminary results of this action were presented at the Gordon Research Conference on single cell biology in May 2021 in Les Diablerets, Switzerland. This action will be presented at the Connective Tissue Oncology Society (CTOS) in November 2023 in Dublin, Ireland. This is the foremost conference for sarcoma specialists in the world. This action provided the data for further grants in this area. The Behjati group has secured funding from Cancer Research UK (CRUK) and Alice’s Arc to further study these childhood cancers. Despite the global COVID-19 pandemic stalling the project and restricting engagement activities, the research fellow engaged in Black STEM futures to support students of Black heritage who are interested in STEM (science, technology, engineering, mathematics and medicine). Thus, results of this MSCA will be reported in forthcoming papers and conferences describing the aberrant developmental trajectories of childhood sarcoma and atlases normal human bone and muscle development. The action has led to further funding to study childhood cancer. The datasets collected during this MSCA will inform and enhance our understanding of paediatrics, oncology, and developmental biology in the coming years.
This MSCA action has been or will be disseminated in a number of ways, beyond academic publication. The preliminary results of this action were presented at the Gordon Research Conference on single cell biology in May 2021 in Les Diablerets, Switzerland. This action will be presented at the Connective Tissue Oncology Society (CTOS) in November 2023 in Dublin, Ireland. This is the foremost conference for sarcoma specialists in the world. This action provided the data for further grants in this area. The Behjati group has secured funding from Cancer Research UK (CRUK) and Alice’s Arc to further study these childhood cancers. Despite the global COVID-19 pandemic stalling the project and restricting engagement activities, the research fellow engaged in Black STEM futures to support students of Black heritage who are interested in STEM (science, technology, engineering, mathematics and medicine). Thus, results of this MSCA will be reported in forthcoming papers and conferences describing the aberrant developmental trajectories of childhood sarcoma and atlases normal human bone and muscle development. The action has led to further funding to study childhood cancer. The datasets collected during this MSCA will inform and enhance our understanding of paediatrics, oncology, and developmental biology in the coming years.
This MSCA has pushed single-cell biology and paediatric oncology forward in a number of ways. Single-cell sequencing offers unprecedented resolution, thereby contributing to exploring effective personalised therapeutics in the form of human atlases and cancer research. Due to the rarity of these diseases and lack of funding for paediatric research, this has only been attempted in few childhood tumour types and MSCA has contributed significantly towards this effort. The results from this action shed light on how childhood cancers arise in the context of aberrant foetal development. Furthermore, these atlases are being leveraged therapeutically by identifying new targets for therapy for paediatric patients. This has immense socio-economic and societal implications, as these patients may live longer more fulfilling lives as UK citizens. If successful, these approaches can be applied to EU citizens and other paediatric patients, globally. These atlases and therapies may also influence the investment landscape of immune therapy targets. The current market for T-cell immunotherapies, such as Chimeric Antigen Receptor (CAR) T-cell therapy, is rapidly increasing. Investments in the biopharmaceutical industry space has led to promising scientific advancements for patients and financial advancements for industry stakeholders.