Winning Projects

– Memory and/or Peace

Armelle GOSSELIN-GORAND

CMAP : Chaire Mémoire et avenir de la paix

Since wars begin in the minds of men, it is in the minds of men that the defences of peace must be constructed”. In line with this Unesco motto, the “Memory and Future of Peace” Chair aims to question and analyse the conditions for peace and peacekeeping in order to better build the future and meet the challenges of the contemporary world. A laboratory of ideas and experimentation, this programme is based on research in law (public, private, history of law and political science), history and neuropsychology, and on the experience of a region, Normandy, that was strongly marked by the Second World War. The remembrance approach, at the heart of this Chair, is rooted in a forward-looking objective to provide a better foundation for and forge peace in a context of strategic change. The aim is to base legal and historical research on neuropsychological data to better understand the consequences for victims, including in a transgenerational dimension, and to build a ‘memory of the future’ of peace. The project aims to consider individual and collective memory, based on the contributions of neuropsychological work on traumatic memory. It will also consider the impact on the conditions for peace and the question of the peaceful settlement of disputes imposed by the United Nations Charter, which implies a special role for justice, whether criminal (internal/international), civil or transitional, questioning the need to judge. The Chair is also committed to questioning the conservation of peace and the requirements of peace in order to contribute to the development of an education and a culture of peace, in a contemporary society that is increasingly inclusive and dependent on new technologies.

Peggy QUINETTE

MEMOIRE(S) :  Mémoriser l’Histoire : La Libération de la Normandie comme composante de l’identité individuelle et collective

The Liberation of Normandy is a major collective event in world history, one that has been extremely well documented historically and plays a major role in “remembrance tourism”. While it may have been perceived as a traumatic event for the people of Normandy, characterised by sadness and mourning for the loss of life and the towns destroyed by the bombardments, in the collective mind it symbolises the liberation and disappearance of the enemy from the land and peace for the rest of France, and more broadly the end of the war and the defeat of the Nazis. Today, commemorative events play an important role in our society, paying tribute to the victims and preserving the history of the region. The commemoration of the eightieth anniversary of the D-Day landings will very soon lead to unprecedented media exposure of the Normandy region and to reminiscences of the events of the Second World War in the minds of Normandy’s witnesses and, more broadly, in those of the French people. The scientific literature on autobiographical memory highlights two critical periods in the link between memory and identity. Childhood and adolescence, when identity is formed and stabilized on the basis of lived experience, and old age, which is particularly conducive to making sense of events experienced throughout life. The survivors of the Liberation of Normandy are a population of interest for the study of the relationship between memory and identity: as children, these people directly experienced the Liberation of Normandy and the potentially traumatic Allied bombardments, and now they are reaching old age where reminiscences and the desire to pass on memories predominate. This project is a unique opportunity to gather the accounts of the last direct witnesses (from Normandy) and indirect witnesses (from outside Normandy) of the Liberation and to try to understand, through individual life stories, how a major potentially traumatic collective event affected these people throughout their lives and shaped their identity. The testimonies collected will constitute raw material of inestimable value from a scientific and heritage point of view, and will require a cross-disciplinary approach in order to understand how the events of the Liberation of Normandy profoundly affected these populations and how resilience developed through individual experiences.

Thomas HINAULT

VRTIME : Virtual reality modulations of the perception and memory of time

The temporal dimension of our perceptions and memory is central in the adaptation to a constantly accelerating world, with its everincreasing demands. The aim of this project is to bring together a wide range of scientific and technical expertise in the fields of temporal processing and Virtual Reality (VR) at the heart of the Normandy research ecosystem. VRTIME proposes to initiate an innovative research topic combining fundamental explorations and clinical applications: the use of virtual reality to study the perception and memory of time, a mechanism at the heart of normal and pathological cognitive functioning, yet traditionally understudied because of difficulties in evaluation that immersive technology can overcome. VR offers unique possibilities for creating modified environments that modulates our relationship with time, while retaining both an ‘ecological’ dimension, i.e. taking into account the interaction between an individual and his or her natural environment, and total experimental control. The VRTIME project involves three work packages (WPs), combining methodological, psychometric and cognitive approaches, and enabling an incremental approach from exploration to validation through to generalization of the research theme. For each of these WPs, healthy adult volunteers will be included. VR data will be collected at the Caen’s Interdisciplinary Centre of Virtual Reality (CIREVE), Europe’s largest research-dedicated VR room (45m2), to which NIMH (U1077, “Neuropsychology et Imagerie de la Mémoire Humaine”) is a board member. The knowledge generated could provide new, clinically effective stratification criteria for personalized prevention and therapeutic management for the benefit of individuals and society. A first WP will ensure that the immersive environments and man-machine interaction are suitable for the scientific study of the subject and do not produce any particular methodological biases. A second WP will involve exploring the relevance of VR and the ecological dimension it provides for not only assessing but also inducing causal alterations in temporal judgement. A series of experimental situations will be tested in order to determine which are most suitable for assessing the perception of time. Finally, a third WP will consist in assessing the developed VR tools for modulations of temporal processing, based on the results of WPs 1 and 2, in a more diverse sample of participants. This will, for the first time, enable to quantify the effects of ageing on VR situations. The aim of this research project is to initiate and develop an innovative research topic fully integrated into the local ecosystem, by combining two key areas of scientific innovation in Normandy: memory and VR. More broadly, the project draws on the NIMH laboratory’s recognized expertise in the study of human memory, as well as the complementary strengths of the COMETE laboratory and CIREVE in VR technology. This collaboration promises to make substantial and complementary contributions in terms of methodology and technology (development of new VR environments specifically dedicated to the modulation of temporal processing, implementation of new modulation tools), theory (identification of factors associated with modulations of temporal processing), clinical (characterization of sub-clinical parameters associated with effects obtained in VR), psychometric (development and dissemination of validated and standardized time evaluation tools), and institutional (deepening the NIMH – COMETE – CIREVE partnership and the use of VR in investigating human memory). This collaboration will bring together the scientific, technical and methodological expertise required to ensure the success of the project. The prospects associated with this collaboration are numerous, and concern both the study of other aspects of human memory in VR and the investigation of the effect of pathologies on temporal processing.

– Biodiversity and the climate risks

Bastien LEMAIRE

SEPIASpeak : Synthesizing Ethology and Programming for an Integrative Analysis of Sepia officinalis communication 

Decoding the signals used by animals to communicate has long fascinated both scientists and the general public. This task becomes particularly challenging when studying species whose sensory worlds are vastly different from ours such as cuttlefish. If this species intrigues us, it’s undoubtedly because they are phylogenetically distant from us and we still do not fully understand how they communicate.

Previous research has shed light on how cuttlefish use mostly visual signals displayed on their skin and specific arm postures for communication. However, acquiring comprehensive knowledge is challenging due to the cuttlefish’s elusive nature and camouflaging capacities, their sensitivity to environmental disturbances, and the complexity of having cuttlefish interact with each other in a laboratory setting. This makes extended observation and communication studies in the wild or controlled environments difficult.

However, recent progress in robotics holds a solution. Biomimetic robots, more naturalistic than ever, can enter the sensory world of these phylogenetically distant species to interact with them. Such a feat was recently showcased in the BBC wildlife documentary where a biomimetic cuttlefish interacted with wild cuttlefish looking for reproductive partners along the Australian coasts. When this biomimetic model displayed aggressive patterns on its skin screen, a surrounding male elicited a similar pattern and even interacted with it, touching it. Interestingly, when the model exhibited a female pattern, the male cuttlefish attempted copulation and guarded it from other approaching males. This instance serves as one among many proofs of concept demonstrating how biomimetic models offer insights into animal behaviour.

This project aims to harness this technology and adapt it to our scientific needs, enabling systematic studies of cuttlefish communication with conspecifics. Initially, we will design and build a biomimetic cuttlefish capable of mimicking real cuttlefish motion in water, changing skin patterns through integrated screens, and adjusting arm posture. This model will then be employed to identify visual patterns used by cuttlefish for sex recognition and to observe how changes in skin patterns and arm postures influence interactions in a laboratory setting. Building upon this, we intend to integrate an artificial intelligence network into our biomimetic model in the project’s final phase. This AI will automate the recognition and response to cuttlefish in the laboratory, serving as a groundbreaking proof of concept for subsequent studies in natural settings.

This interdisciplinary project, merging ethology, robotics and computer science, aims to shed light on the social behaviours and communication strategies of cephalopods. Its success could lead to significant advances in our understanding of these species and contribute broadly to the fields of behavioural ecology, robotics, and beyond, illustrating the potential of innovative technology in the study of behaviour and animal communication.

Bernadette TESSIER

ESTUARIX : Estuaries under climatic risks. Lessons from the recent past

All environmental compartments of the planet, from the deep oceans to the headwaters of watersheds, are now impacted by climate change, affecting both their geomorphological, sedimentary, and ecosystem functions. Estuarine zones are particularly vulnerable, as they are at the confluence of changes occurring across watersheds, coastal areas, and oceanic systems. Given their major socio- economic and ecological importance, estuaries face a range of risks exacerbated by climate change and increasing anthropogenic pressures, including submersion, erosion, flooding, siltation, and salinization.

The objective of the Estuarix project is to investigate the impacts of these pressures on the morpho-sedimentary dynamics of estuarine systems, and on associated anthropogenic landscape transformations, through the lens of the transition to the “Anthropocene”, a shift from natural climatic regimes to those driven by global change. This transition, initiated in the 19th century, corresponds both to the end of the Little Ice Age, a cold and stormy natural climatic episode, and the onset of major coastal engineering works, followed in the early 20th century by the emergence of anthropogenic climate change.

Estuarix aims to decode estuarine responses to these past upheavals by examining high-resolution sedimentary archives. Sediment cores collected from estuarine environments will be analyzed to reconstruct environmental signals over time, including parameters such as sediment texture and grain size, geochemical composition, and other indicators directly linked to morphological and hydro- sedimentary processes.

A distinctive feature of the project is its interdisciplinary approach, combining sedimentology, geochemistry, geochronology, and geo- history. By integrating geohistorical data, the project will contextualize estuarine responses in relation to evolving human activities across the contributing watersheds.

Accurate chronological control is essential for interpreting these sedimentary signals, especially in relation to climate variability and human-induced transformations. Estuarix will establish a high-resolution chronology with decadal precision using two complementary dating methods: 1) 137Cs and 210Pbexc analyses, which are effective for dating sediments deposited within the last 100–150 years.

2) Optically Stimulated Luminescence (OSL), which makes it possible to quantify the dose of natural radioactivity that quartz grains store when they are buried. Recent work demonstrates the enormous potential of this method to date with very good precision estuarine successions dating back several centuries.

By combining these chronological tools with environmental proxies, the project will reconstruct evolutionary dynamics of estuaries over the past two centuries, with a focus on recent decades and the acceleration of change.

The results of this retrospective analysis will provide key insights into the effects of climate change, particularly extreme events (e.g.storms and floods), and anthropogenic pressures. These findings will serve as a scientific basis for projecting estuarine responses under future climate scenarios.

Estuarix will initially focus on sediment archives already collected from several estuaries in Normandy, enabling comparative analyses to distinguish local responses from broader regional or global drivers. The project is supported by a consortium of researchers with a strong history of collaboration on the study of estuary trajectories since the Little Ice Age. This established expertise represents a strategic advantage for leading Estuarix and will serve as a foundation for preparing a larger, internationally focused initiative (e.g., an ERC Synergy Grant). The envisioned follow-up project will extend the approach to multiple Atlantic estuarine and coastal sites, using very high-resolution OSL dating to analyze recent sediment archives and support robust projections of future coastal system behavior.

– Artificial intelligence

Frédéric JURIE 

CAI4Science – AI for Science at Caen

CAI4Science (AI for Science in Caen) is an ambitious research project that aims to harness the transformative potential of artificial intelligence (AI) to accelerate scientific discovery across various fields. The project brings together the expertise of four research laboratories at the University of Caen Normandie (CIMAP, CRISMAT, LPC, and GREYC) to develop and deploy advanced AI/machine learning technologies tailored to the specific needs of the domain sciences. The main research thrusts include: the integration of physical models and machine learning, the use of foundation models for scientific discovery, the development of surrogate and generative models for scientific simulations, as well as fundamental advancements in core AI areas such as optimization, interpretability, and robustness. The project also aims to train and disseminate these innovations to the scientific community through summer schools, workshops, and doctoral programs.

Gaël DIAS

MENTAL.AI@CaeSAR : Artificial Intelligence for Mental and Brain Health

Psychiatric disorders, such as major depressive disorder, bipolar disorder, schizophrenia, anxiety disorders or post-traumatic stress disorder affect millions of people worldwide, often leading to profound personal suffering and societal burdens. Similarly, neurodegenerative diseases like Alzheimer’s, Lewy body dementia, Parkinson’s, amyotrophic lateral sclerosis, and frontotemporal dementia pose significant challenges, with limited effective treatments available to slow or halt disease progression. In particular, it has recently been evidenced that neuropsychiatric disorders are today’s most important group of illnesses.

In recent years, the intersection of artificial intelligence (AI) and healthcare has sparked a revolution, offering unprecedented opportunities to transform the diagnosis, monitoring, and treatment of psychiatric disorders and neurodegenerative diseases. As we stand on the brink of a new era in medicine, it is crucial to recognize the potential of AI-powered digital tools in addressing the complex challenges faced by individuals living with neuropsychiatric disorders.

The traditional approach to diagnosing and managing these conditions has often been reactive rather than proactive, relying on subjective assessments and limited treatment options. However, the emergence of AI-powered digital tools offers a paradigm shift towards a more personalized, predictive, preventive, and participatory model of care, so called 6P medicine.

By harnessing the power of artificial intelligence, researchers and clinicians can now analyze large amounts of data, including digital markers and biomarkers, to identify subtle changes indicative of disease onset or progression. This constant monitoring is crucial for initiating interventions at a stage when treatments may be most effective (just-in-time intervention), potentially altering the course of the disease and improving outcomes for patients.

However, realizing the full potential of AI-powered digital tools for mental and brain health requires collaborative efforts across disciplines, including medicine, computer science, cognitive sciences, linguistics and ethics. It demands rigorous validation and explanation of algorithms, robust safeguards for patient privacy and data security, and equitable access to technology for all individuals, regardless of socioeconomic status or geographic location.

The MENTAL.AI@CaeSAR project aims to build the foundations of a long-term pluridisciplinary research effort to develop AI-powered 6P medicine within the domain of mental and brain health by improving early detection, monitoring, diagnosis and treatment as well as providing new tools for medical care administration. In particular, it gathers five research laboratories from the University of Caen Normandy (GREYC UMR 6072, NeuroPresage UMR-S 1237, NIMH UMR-S 1077, CRISCO UR 4255 and ICREJ UR 967) and the GIP platform CYCERON, five national research laboratories (LIS UMR 7020, ETIS UMR 8051, LIA UPR 4128, LORIA UMR 7503, STL UMR 8163), four international Institutions (University of Tartu – Estonia, Queen’s University of Belfast – UK, University of Beira Interior – Portugal, Indian Institute of Technology Patna – India) and one company (ForLabs).

In conclusion, the study and development of AI-powered digital tools for psychiatric disorders and neurodegenerative diseases represent a groundbreaking frontier in healthcare, offering hope for millions of individuals affected by these conditions. By embracing innovation, fostering collaboration, and prioritizing patient-centered care, we have the opportunity to revolutionize mental and brain health for generations to come.

The BREAKTHROUGH project contributes to the quality of large language models in terms of (varieties of) languages, as well as the quality of their automatic an-notation, in order to solve the crucial problems of what might be called noisy data – the narrowness of the practices represented, and the still approximate nature of enrichments.

The advances represented by large language models, as symbolized by ChatGPT, depend on the possibility of megadata-based training. Such megadata are only available for a subset of languages. For historical French, there are no models available for the period between 1500 and 1900; for the linguistic varie-ties of Northern and even Southern France, some models are being developed, but on a very limited empirical basis; for contemporary French, it is mainly for-mal writing that has been analyzed, rather than spontaneous speech. Gaps are often filled by recourse to existing models for nearby languages, for which the analyzed varieties constitute noisy environments: the distance between the ana-lyzed varieties and existing models for other languages thus requires considera-ble investments of time and energy on the part of human users to correct the syntactic annotation. Yet advanced annotation of linguistic data is essential not only for language study and computer sciences, it also has a considerable poten-tial industrial impact in the fields of user identification, opinion and argumenta-tion mining, and idiomatic translation, including for varieties which only have a limited place in the digital world.

The BREAKTHROUGH project aims to optimize advanced annotation through noisy data. Through three study programs, it proposes to test processing hypotheses to reduce human involvement in the production of annotated corpo-ra, through model adaptation. The aim is to consider 1. historical states of lan-guages; 2. spontaneous oral data; 3. less-documented (varieties of) languages. Working in parallel on three types of noisy data enables us to develop protocols and test their robustness. The current hypothesis relies both on sampling prob-lematic structures for fine-tuning, and on the potential ability to manipulate the parser to focus on such problematic structures, in either case to limit erroneous analyses based on linearity alone. In addition to the noise generated by model adaptation, the field also suffers from a diversity of annotation formats and practices, which we aim to reduce at the very least by creating tools that enable bridging, or at best to eliminate by creating consensus. The international team we have assembled, and the experience of the project leader, mean that we are confident of successfully meeting challenges, and achieving the envisaged deliv-erables, which are

• An efficient protocol for advanced annotation of noisy environments
• Optimally annotated corpora deposited on the international UD platform
• Availability of advanced tools on the project GIT
• At least 3 articles in high-profile journals on adaptation protocols and conver-gence of practices and formats
• Training sessions in 6 leading European and North American research centers
• The development of a major ERC Advanced Grant application.

In this way, we will bring to fruition the potential of artificial intelligence for ad-vanced data annotation in noisy environments that define the innovative and original character of the BREAKTHROUGH project.

– Innovation in healthcare

Elie BESSERER-OFFROY

Concerto : Collaborative Network for Cancer Radionuclide Therapy Development

Personalized medicine offers hope for cancer patients by providing a tailored approach to treatment that takes into account the unique characteristics of each patient’s tumor. This approach can lead to improved efficacy, reduced side effects, and the ability to overcome resistance mechanisms, potentially leading to new treatment paradigms and improved patient outcomes, especially for aggressive cancers with poor prognosis. This is one of the vision of an exciting new field in cancer research called radiotheranostics, which is set to transform oncology. At the heart of this innovation are G protein-coupled receptors (GPCRs), a family of receptors that play a pivotal role in various physiological processes and, as it turns out, in cancer development too. Certain GPCRs are overexpressed in many types of cancers, making them prime and promising targets for radionuclide therapy (RNT) due to their accessibility on the cell surface. Our international consortium, bringing together four major academic centers, is at the forefront of this research, developing novel peptide-based radiotheranostic probes that can seek out these overexpressed GPCRs and deliver a one-two punch: first, by detecting the cancer cells with diagnostic imaging, and then by hitting them with targeted radiation therapy. This dual-action approach promises a more precise, effective, and personalized treatment for cancer patients. This powerful pairing of diagnosis and therapy has already shown remarkable success in treating challenging cancers like prostate cancer and neuroendocrine tumors.

The journey of these RNT probes from the lab to the clinic is a story of innovation and collaboration. By improving their plasma stability and ensuring they can reach the tumor, our team is overcoming significant challenges in drug delivery. The probes are designed to be versatile, compatible with different types of diagnostic and therapeutic radionuclides, and tailored to the specific needs of each cancer type. This research proposal focuses on the development of novel peptide-based RNT probes targeting three highly overexpressed G protein-coupled receptors (GPCRs) in some of the most challenging malignancies: the apelin receptor (APJ) in ovarian cancer and glioblastoma, the neurotensin receptor 1 (NTSR1) in ovarian cancer and prostate cancer, and the ghrelin receptor (GHSR) in prostate cancer and glioblastoma. However, RNT also faces some challenges, such as resistance phenomenon. To overcome this problematic issue, our group aims to investigate the combination of RNT with clinically approved drugs. These combinations provide hope to increase DNA damage and enhance anti-tumor immune responses, potentially improving the efficacy of RNT and preventing the emergence of resistance. By leveraging cutting-edge chemistry, molecular biology, and advanced imaging techniques, this collaborative effort aims to revolutionize precision oncology and deliver more effective, personalized cancer treatments to patients in need. This project is not just about developing new treatments; it’s about creating a new paradigm in cancer care that could significantly improve patient outcomes. It’s a beacon of hope for those facing aggressive cancers, and a testament to the power of international collaboration in the fight against this global health challenge. Beyond its research, our consortium believes that knowledge transfer and communicating on research to broader audiences beyond their peers, is of major importance for society. For this reason, the creation of a new summer school program that aims to provide participants with the skills, tools, and hands-on experience to become effective science communicators is an integral part of this research proposal.

Samuel VALABLE

TargetedNanoOnco : Functionalized Multimodal therapeutic nanoparticles to synergize radiotherapy and immunotherapy in Glioblastom

High-grade brain tumors, mainly represented by glioblastoma, are aggressive tumors characterized by their resistance to conventional treatments such as radiotherapy and chemotherapy. This results in a very short survival expectancy. The lack of oxygen in glioblastoma as well as the presence of immunosuppressive cells are key elements responsible for the poor response to treatments. We have initiated a project aiming to address these issues in a concomitant way by means of custom nanoparticles containing gadolinium to increase the effects of X-rays, manganese used to locally increase the oxygen concentration as well as immunotherapies to reprogram the immunosuppressive macrophages. This project builds on our previous work having demonstrated that these nanoparticles accumulate in glioblastoma after systemic administration. However, after intravenous injection, the quantity of nanoparticles accumulating in the tumor could be limited by the presence of the blood-brain barrier as well as by the cellular membranes of the cells of interest, namely tumor cells and macrophages. The project that we are proposing here aims to take advantage of a flaw in this system, namely the overexpression of adhesion molecules specifically on the tumor site, P-selectins, but also the overexpression of mannose receptors specific to immunosuppressive macrophages. The nanoparticles (NPs) that will be used are zeolites, porous nanocrystals with ordered pores and cages that give them high efficiency in the capture and transport of small drug molecules. Thus, these NPs will be exploited in a as multimodal therapeutic NPs called MTNPs and functionalized by means of molecules directed against the proteins overexpressed in the tumor and in tumor.

Anne Sophie VOISIN-CHIRET

CAR-DD : Cancer Advanced therapy through Rational Degrader Design

The CAR-DD project aims to develop a new generation of anticancer drugs known as degraders (PROteolysis Targeting Chimeras, or PROTACs). These innovative molecules do not merely block a target; they induce its complete destruction through the cell’s natural recycling system, called the proteasome. In this project, the target is Mcl-1, a protein that protects cancer cells from cell death. Overexpression of Mcl-1 is frequently observed in several types of cancer, including ovarian, lung, lymphoma, and pancreatic cancers, and constitutes a major mechanism of resistance to conventional therapies. Current Mcl-1 inhibitors have shown important limitations, particularly cardiac toxicity. Degraders offer a promising alternative to selectively eliminate this protein in tumor cells while minimizing side effects. The CAR-DD project, led by the Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN) within the University of Caen Normandy, builds on very encouraging results obtained with a first generation of patented degraders that demonstrated activity in chemoresistant ovarian cancer cell models. CAR-DD aims to go further by designing degraders that are even more effective, selective, and safe. This will be achieved by combining molecular modelling, artificial intelligence, and medicinal chemistry approaches, while exploring new cellular enzymes known as E3 ligases, capable of initiating protein degradation. The candidate drugs will first be tested on cancer cell lines and then on patient-derived tumor organoids. The project is structured into six complementary components. The first focuses on the design of degraders using molecular modelling tools and will be carried out at CERMN. The second concerns the chemical synthesis of the compounds, conducted at CERMN and Imperial College London. The third involves the biophysical and pharmacological characterization of the molecules, particularly their solubility, permeability, stability, and the identification of the ternary complex through protein–protein interaction measurements. This work will be carried out at CERMN in partnership with the IMPACT platform (CRCI2NA – UMR_S 1307– INSERM) in Nantes and the Department of Molecular Biotechnology at the University of Turin. The fourth component will assess the biological efficacy of the candidates, both on cancer cell lines (at INSERM U1086 ANTICIPE in Caen and at Josep Carreras Leukaemia Research Institute in Barcelona) and on patient-derived organoids through the interregional ORGANO network. The fifth component focuses on the scientific dissemination of the project, including publications, patent filings, and the organization of an international summer school entitled “PROTAC 2.0” in 2027. Finally, the sixth component is dedicated to outreach and engagement with society, through workshops, conferences, and educational materials intended for the general public. This organization ensures a smooth progression from basic research to clinical application by combining high-level academic expertise, regional structuring, and European visibility. Through its therapeutic ambition, collaborative approach, and societal engagement, CAR-DD is fully aligned with the objectives of the CaeSAR funding call, positioning Normandy as a key player in health innovation.

Siamak HAGHDOOST

PancResist : Strategies to Overcome Radioresistance in Pancreatic Cancer: A Collaborative Approach Targeting Cancer Stem Cells, Gene Pathways combined with Hadron Therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide due to its late diagnosis, early spread, and strong resistance to current treatments like chemotherapy and radiotherapy. Standard X-ray radiotherapy often fails to control PDAC because the tumor contains special cells called cancer stem cells (CSCs), which are highly resistant to radiation and drive tumor relapse. Our project aims to develop a new, more effective treatment strategy for PDAC by focusing on these resistant CSCs and using advanced radiation therapies called hadrontherapy (HT), including proton therapy and carbon ion radiotherapy (CIRT). Unlike conventional X-rays, hadrontherapy delivers highly precise, powerful radiation that causes complex DNA damage in cancer cells, making it harder for them to repair and survive, especially the resistant CSCs. CSCs survive radiation because they have strong antioxidant defenses regulated by a protein called Nrf2, and they thrive in lowoxygen (hypoxic) environments where other proteins called Hypoxia-Inducible Factors (HIFs) help maintain their stem-like and resistant nature. CSCs also possess efficient DNA repair systems that help them fix radiation damage. By targeting Nrf2, HIFs, and DNA repair pathways simultaneously, we hope to weaken these defences, increase cancer cell death, and reduce the chance of tumor relapse. Our research involves isolating CSCs from pancreatic cancer cell lines and patient-derived tumors to study their behaviour and resistance. We will test different radiation types X-rays, protons, and carbon ions to see which is most effective against CSCs. Using cutting-edge gene-editing tools like CRISPR, we will precisely inhibit Nrf2 and HIF proteins and combine this with DNA repair inhibitors to amplify the effects of radiation. Additionally, this project will explore how these treatments influence the immune system’s ability to fight cancer. PDAC often suppresses immune responses, but advanced particle radiotherapy may help stimulate anti-tumor immunity, especially when combined with inhibitors targeting tumor microenvironment factors. Finally, we will translate our laboratory findings into animal models of pancreatic cancer to test the best treatment combinations in living systems. By monitoring tumor growth, immune responses, and survival, we aim to identify new therapies that can ultimately improve patient outcomes. This interdisciplinary project brings together experts in cancer biology, radiation physics, immunology, and molecular genetics across multiple institutions. It addresses a critical need for novel approaches against PDAC’s resistance and poor prognosis by integrating innovative radiation techniques with targeted molecular therapies and immunomodulation. Through this comprehensive strategy, we aspire to pave the way for future clinical trials, offering hope for more effective and personalized treatment options for pancreatic cancer patients.

Aurélien JUSTET

SomaFibRad : Cancer Advanced therapy through Rational Degrader Design

Pulmonary Fibrosis (PF) describes a chronic lung disease in which lung tissue becomes scarred over time. This condition ultimately leads to chronic respiratory failure creating and eventually death within 2-5 years after the diagnosis in patient with Idiopathic Pulmonary Fibrosis (IPF), one of the most frequent diseases among PF. While lung fibrosis can be idiopathic or triggered by various factors, such as radiation, the interplay between genome instability, somatic mutations, and their impact on lung tissue integrity and fibrosis progression remains an underexplored research domain. Our preliminary results suggest a significantly increased rate of somatic mutations in IPF as compared to controls. We hypothesize that these mutations trigger molecular cascades that ultimately lead to the fibrotic remodeling of lung parenchyma. We propose to use radiation as a controlled tool to induce fibrosis, genome instability, and somatic mutations in lung tissues. The originality of the proposal lies in the combined use of an original ex vivo model based on Human Precision Cut Lung slices culture, a radiation-induced murine lung fibrosis model, and the application of cutting-edge technologies to assess the effect of radiation on the cellular transcriptomic signature but also the validation of this mutation signature in a real-life cohort in collaboration with internationally renowned experts in the field of lung fibrosis, transcriptomics and genetics. By incorporating genomic analysis and transcriptomic analysis we aim to establish the connection between hypoxia, aging, and radiationinduced somatic mutations and the development of lung fibrosis. This integrated approach will provide a comprehensive understanding of the genomic alterations associated with radiation-induced fibrosis, facilitating the identification of novel therapeutic targets and personalized treatment strategies for patients affected by this condition. The feasibility of this project relies on the collaboration of internationally recognized multidisciplinary experts in various fields, including cellular effects radiation, hypoxia, bioinformatics analysis, multi-omic approaches applied to pulmonary fibrosis, and genetics of these pathologies. Securing funding would provide crucial assistance in accelerating the acquisition of robust preliminary results, notably in establishing the model through the recruitment of a postdoctoral researcher to apply for an ERC Starting Grant within two years. In a medium-term perspective, this funding will also have a significant impact on the establishment of a team focused on fibrogenesis, led by Dr. Justet within the ISTCT.