Dr Celio POUPONNOT (Curie, Paris)

Dr Celio Pouponnot, can you introduce yourself in a few lines? (your role and activity within the Curie Institute)

I am a research director at the CNRS and lead a research team of 12 to 14 people, on the Orsay site of the Curie Institute which is spread over three sites: Paris, Orsay, Saint-Cloud. Our research activities focus on childhood brain tumors and their treatments, in particular radiotherapy. A significant part of our work concerns medulloblastoma, a pediatric tumor of the cerebellum on which the funded project focuses. Medulloblastoma is mainly pediatric, diagnosed at a median age around 7 years. The 5-year survival is 70-80%. However, this statistic masks the great heterogeneity of these cancers, which presents variable risk groups including low or high risk tumors, the survival rate of the latter being much lower.

You are the originator of the project “Modeling of medulloblastoma using human cerebellar organoids and analysis of the effect of agricultural pollutants”. Can you explain the main reasons that prompted you to write this project? What are its objectives?

The project supported by Grandir sans Cancer and Eva pour la vie is led by B Duvillié, an INSERM researcher in the team. It is structured around two axes, the development of a model to study high-risk medulloblastoma and a second where we use this model to study the effect of pollutants on the early phases of the tumor process, i.e. its initiation.

Study models are key elements in cancer research because they allow us to study different processes. In this project, B. Duvillié develops an in vitro mini-organ model, in culture dishes. By using immature human cells, called induced pluripotent stem cells, we can obtain a 3-dimensional structure that resembles a mini-human cerebellum. By introducing genes altered in medulloblastoma, we are able to model high-risk medulloblastoma. Even if it has its own limitations like any study model, it allows us to study the initial stages of tumorigenesis and the effects of pollutants on these initial stages.

In the first part of the project, we are looking to improve this model by adding cells that form blood vessels to bring it closer to the real organ. In the future, we will add immune cells to better understand their role in tumor initiation, the response to anti-cancer therapies or their impact in the event of exposure to pollutants.

In the second part of the project, we will analyze the impact of certain pollutants (household insecticides, agricultural antifungals) on the early stages of medulloblastoma initiation. The role of pollutants in the onset of childhood cancers is an important societal issue, as we have seen recently, but only partial scientific answers have been provided. As researchers, our role is to advance science on fundamental and clinical research issues but also, when we can, on these societal debates. Our work on pollutants is part of a broader framework. Indeed, various research teams are working on these issues, including the PEDIAC consortium in which we are involved and whose themes focus on the causes and origins of pediatric cancers. This consortium makes it possible to combine epidemiological studies and experimental research. We hope to be able to contribute to providing even partial answers to these important questions about the potential involvement of pollutants in childhood cancers.

What are the prospects and your hopes for the outcome of your research project?

We hope to improve the models for studying medulloblastoma by getting as close as possible to the pathology and share them with the scientific community. These models should allow us to better understand this pediatric pathology, in particular its causes and thus contribute to better treating it. Concerning pollutants, we hope that our research will contribute to clarifying their potential impacts in pediatric cancers. Our experimental study will not provide definitive answers but could provide bundles of indications on the potential of pollutants to modify the cell of origin of these cancers and thus participate in the initiation or acceleration of the cancerous process. It will be essential to complete our study with more complex in vivo models that can provide additional answers. Our study is part of a multidisciplinary field including epidemiology, toxicology (…) which, all together, should contribute to providing answers to these important societal questions.

Generally, parents of children with cancer wonder about the causes of this disease, the incidence of which is not decreasing in France or in Europe. While in 10% of cases, genetic factors are identified, in the vast majority of cases, doctors do not know the causes. Many parents wonder about environmental factors and pollutants, while having a certain feeling of helplessness, because what can be prevented, unlike adults, in children who do not drink alcohol, do not smoke, who eat properly and who exercise? What would you like to say to these parents?

It is important to specify that the 10% of genetic factors in question concern hereditary predispositions or congenital mutations. Nevertheless, frequent genetic alterations are identified in pediatric cancers such as mutations, chromosomal alterations, etc. These so-called "somatic" genetic alterations are clearly involved in the cancerous process, are very frequent and found in almost all adult and pediatric cancers. The scientific challenge lies in understanding the origin of these alterations: are they caused by environmental factors or do they appear randomly? Scientific studies have shown that these genetic alterations are much more frequent in organs undergoing strong proliferation/growth. One of the characteristics of children's organs is precisely this significant growth/proliferation. It is therefore likely that some of these somatic alterations are explained by this phenomenon. At the same time, studies have established, for example, that exposure to ionizing radiation or living near large wine-growing areas increases the risk of pediatric cancers. The environment and exposures must therefore not be neglected, and more research is needed to clarify their role and contribution. This is precisely the aim of our project.

Beyond the call for public generosity, Eva pour la vie has been driving forward an unprecedented approach in Europe since 2012 – now shared by many associations and professionals through the Grandir Sans Cancer federation – aimed at obtaining a fund from the State dedicated to research into childhood cancers, as well as improved assistance for families of sick or deceased children. With Grandir Sans Cancer, she obtained at the end of 2018 from the Ministry of Research an annual fund of €5M/year dedicated to basic research into childhood cancers, and at the end of 2021, a one-off contribution of €20M to promote the structuring of research teams on pediatric cancers. She is also closely linked to several social advances for the families concerned. She is currently mobilizing parliamentarians so that the research fund is increased to €20-25M/year in order to include pediatric oncologic clinical research. She hopes that the mobilization of public authorities will be sustainable, stable and focused, at the same time, on research, care, prevention and social support that meets needs. What do you think of this approach?

In recent years, public support for pediatric cancer research has been strengthened thanks to the mobilization of associations. The funds obtained have made it possible to mobilize new research teams on these themes. Research is becoming increasingly expensive. These funds are therefore crucial to develop ambitious and quality pediatric cancer research in order to understand the causes, the biology of pediatric cancers, but also the impact of exposure to pollutants, the mechanisms of resistance to treatments and their toxicities, etc. The diversity and combination of approaches (clinical, epidemiological, toxicological, fundamental) is necessary to progress in the understanding of these pathologies. It is therefore essential that these initiatives continue and be heard because the funds they have made it possible to release represent essential assistance for the advancement of pediatric cancer research.