Training European Experts in Multiscale Studies of Neural Crest Development and Disorders: from Patient to Model Systems and Back again.

Project Information

NEUcrest

Grant agreement ID: 860635

DOI

10.3030/860635

Project closed

EC signature date 4 September 2019

Start date 1 November 2019

End date 30 April 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 4 156 404,84

EU contribution

€ 4 156 404,84

Coordinated by

INSTITUT CURIE
France

Periodic Reporting for period 2 - NEUcrest (Training European Experts in Multiscale Studies of Neural Crest Development and Disorders: from Patient to Model Systems and Back again.)

Reporting period: 2021-11-01 to 2024-04-30

Summary of the context and overall objectives of the project

The neural crest (NC) lineage, deriving from the multipotent and migratory embryonic NC cell population, contributes to form the peripheral nervous system, craniofacial structures, pigment cells and many other tissues and organs in vertebrates, from lamprey to human. Anomalies in NC formation are associated with approximately one third of human congenital malformations and syndromes such as cleft lip/palate, syndromic craniosynostosis, Hirschsprung Disease, Waardenburg syndrome and Pierre Robin Sequence. Furthermore, in Europe, cancers of NC derivatives, e.g. neuroblastoma, pheochromocytoma and malignant melanoma cause 7-10% of childhood cancers and 3-7% of cancer deaths respectively. Thus, diseases of NC-derived tissues, referred to as neurocristopathies, are an acute societal problem. Due to the complexity of these tissues, understanding the underlying causes and mechanisms requires multi-disciplinary expertise. To address this, we require the dedicated training of a new generation of scientists and clinicians, working with academia and industry. Only in this way can we broaden our scope, working power and understanding of the impact of neural crest biology in health and disease. The NEUcrest project aimed at training 15 ESRs within a novel, ambitious and interdisciplinary research program, which main objectives were 1) to undertake an integrated gene discovery approach in NC development and neurocristopathies; 2) to establish cellular and animal models for neurocristopathies with complementary experimental advantages while implementing ethical recommendations; 3) to analyse the function of genes involved in human neurocristopathies with optimised integrative strategies; 4) to establish reciprocal links between clinical genetics and functional studies of neurocristopathies; 5) to establish biostatistical strategies tailored for NC gene network computational modelling; 6) to optimize NC differentiation from human stem cells in order to reach industrial standards; 7) to establish the best translational strategies for drug screening in NC-related diseases; 8) to disseminate results for implementation of best practices for molecular diagnostic management strategies; and, 9) to increase awareness about neurocristopathies in the general public.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The 15 ESRs recruited into the program have been trained with multidisciplinary experience in gene discovery, in genetics and in vivo phenotyping including active interactions with networks of specialised European clinicians who identify and collect patient samples. The frame of the NEUcrest network has optimized the sharing of precious patient-derived resource for research. While no isolated team can master all the scientific and technical strategies needed for studying each of the complex aspects of NC and tumour formation, NEUcrest has brought together experts in the various facets of NC development and cancer biology to further combine the latest insights into the NC Gene Regulatory Network (GRN), with newly demonstrated links between NC development, NC-derived cancers, and clinical human genetics. NEUcrest has provided a synergistic framework for a comprehensive analysis of the selected genes and biological processes, from patient to animal models and screening and thence back to the clinic with several cellular and animal models employing complementary advantages and the latest technologies in imaging and "multi-omics". Relationships with patient associations/networks, as part of the ESR training, have helped connect research with the general public, while deploying educational material for the benefit of the patient and public awareness. Altogether, the NEUcrest Network has accomplished its goals of excellence by training in science, cross-sector cooperation, and its objective of strengthening links between Science and Society.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

As planned, the network has involved 11 main interacting participants and 9 partners, from hospitals, academic laboratories and SMEs, from 7 European or EU-associated countries: France, Ireland, Spain, The Netherlands, United Kingdom, Austria and Israel. These participants were each expert on a specific aspect of research related to NC. Their cumulative expertise has provided an exceptional environment for ESRs, both for excellent research training and multiple transferable skills. Our ESRs have successfully completed the program with a portfolio of high-quality publications combined with world-leading career development and employability. Among the major scientific and technical advances achieved during the program, we highlight single cell transcriptomic approaches to decipher the programs of NC development, from early patterning to late tissue specification; the programs of normal and pathological epithelial-to-mesenchymal transition; the establishment of robust and scalable protocols to program human stem cells into cranial or trunk neural crest cells; and an innovative melanoma xenograft model in larval zebrafish to explore in vivo human melanoma cell migration. These strategies and new tools have been combined with experimental embryology, molecular biology and biochemistry to understand numerous new and complex functional regulations driving normal and pathological NC/NC-derived cell behaviours. These studies include large-scale gene discovery, the biology of normal and diseased NC-derived cells, and analyses of the impact of the micro-environment during tumour progression of melanoma and neuroblastoma. Those interconnected studies are now being published as the ESRs are defending their thesis work. Over 20 scientific publications will be produced, 6 publications are already accepted for publication in some of the best journals of the field and 12 are in preparation. Furthermore, we had strong emphasis on ESR training for efficient interaction with public and patient associations, which is essential for fostering an improved communication between scientists and society. This has generated new educational and outreach materials (including a wikipedia article and over forty events with various public groups) based on new findings from our ESRs and from their enthusiasm in sharing their scientific life experiences with younger students, patients and the public.

Overall, despite the adverse geopolitical and global health context, the NEUcrest program has overcome all difficulties and fulfilled its goals of training a group of 15 young scientists skilled in neural crest biology and disease, highly aware of the importance of linking Science and Society. The majority of these ESRs will continue pursuing science-related activities. Under the NEUcrest umbrella, all ESRs are tightly interconnected as friends, share an impressive training portfolio, have created a European network of institutes, laboratories, individual established scientists that will enable them to engage in their future careers with full efficiency. Seing this success, it is highly likely that the beneficiary laboratories will soon apply for another ITN program.

Consortium map, models and methodologies