A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Cancer models; Paediatric cancerModelos de cáncer; Cáncer pediátricoModels de càncer; Càncer pediàtricPediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies.This work was supported by grants from Fondation Gustave Roussy; Fédération Enfants Cancers et Santé, Société Française de lutte contre les Cancers et les leucémies de l’Enfant et l’adolescent (SFCE), Association AREMIG and Thibault BRIET; Parrainage médecin-chercheur of Gustave Roussy; INSERM; Canceropôle Ile-de-France; Ligue Nationale Contre le Cancer (Equipe labellisée); Fondation ARC for the European projects ERA-NET on Translational Cancer Research (TRANSCAN 2) Joint Transnational Call 2014 (JTC 2014) ‘Targeting Of Resistance in PEDiatric Oncology (TORPEDO)’, ERA-NET TRANSCAN JTC 2014 (TRAN201501238), and TRANSCAN JTC 2017 (TRANS201801292); Agence Nationale de la Recherche (ANR-10-EQPX-03, Institut Curie Génomique d’Excellence (ICGex); IMI ITCC-P4; The Child Cancer Research Foundation (CCRF), Cancer Council Western Australia (CCWA); PAIR-Pédiatrie/CONECT-AML (INCa-ARC-LIGUE_11905 and Association Laurette Fugain), Ligue contre le cancer (Equipe labellisée, since 2016), OPALE Carnot institute; Dell; Fondation Bristol-Myers Squibb; Association Imagine for Margo; Association Manon Hope; L’Etoile de Martin; La Course de l’Espoir; M la vie avec Lisa; ADAM; Couleur Jade; Dans les pas du Géant; Courir pour Mathieu; Marabout de Ficelle; Olivier Chape; Les Bagouz à Manon; Association Hubert Gouin Enfance et Cancer; Les Amis de Claire; Kurt-und Senta Hermann Stiftung; Holcim Stiftung Wissen; Gertrud-Hagmann-Stiftung für Malignom-Forschung; Heidi Ras Grant Forschungszentrum fürs Kind; Children’s Liver Tumor European Research Network (ChiLTERN) EU H2020 projet (668596); Fundación FERO and the Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Sassella-Stiftung, Berger-Janser Stiftung and Krebsliga Zürich, Deutschland Gemeindienst e.V. and others from Barcelona and province, and No Limits Contra el Cáncer Infantil Association

A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient's tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies

Human Practice. Digital Ecologies. Our Future. : 14. Internationale Tagung Wirtschaftsinformatik (WI 2019) : Tagungsband

Erschienen bei: universi - Universitätsverlag Siegen. - ISBN: 978-3-96182-063-4Aus dem Inhalt: Track 1: Produktion & Cyber-Physische Systeme Requirements and a Meta Model for Exchanging Additive Manufacturing Capacities Service Systems, Smart Service Systems and Cyber- Physical Systems—What’s the difference? Towards a Unified Terminology Developing an Industrial IoT Platform – Trade-off between Horizontal and Vertical Approaches Machine Learning und Complex Event Processing: Effiziente Echtzeitauswertung am Beispiel Smart Factory Sensor retrofit for a coffee machine as condition monitoring and predictive maintenance use case Stakeholder-Analyse zum Einsatz IIoT-basierter Frischeinformationen in der Lebensmittelindustrie Towards a Framework for Predictive Maintenance Strategies in Mechanical Engineering - A Method-Oriented Literature Analysis Development of a matching platform for the requirement-oriented selection of cyber physical systems for SMEs Track 2: Logistic Analytics An Empirical Study of Customers’ Behavioral Intention to Use Ridepooling Services – An Extension of the Technology Acceptance Model Modeling Delay Propagation and Transmission in Railway Networks What is the impact of company specific adjustments on the acceptance and diffusion of logistic standards? Robust Route Planning in Intermodal Urban Traffic Track 3: Unternehmensmodellierung & Informationssystemgestaltung (Enterprise Modelling & Information Systems Design) Work System Modeling Method with Different Levels of Specificity and Rigor for Different Stakeholder Purposes Resolving Inconsistencies in Declarative Process Models based on Culpability Measurement Strategic Analysis in the Realm of Enterprise Modeling – On the Example of Blockchain-Based Initiatives for the Electricity Sector Zwischenbetriebliche Integration in der Möbelbranche: Konfigurationen und Einflussfaktoren Novices’ Quality Perceptions and the Acceptance of Process Modeling Grammars Entwicklung einer Definition für Social Business Objects (SBO) zur Modellierung von Unternehmensinformationen Designing a Reference Model for Digital Product Configurators Terminology for Evolving Design Artifacts Business Role-Object Specification: A Language for Behavior-aware Structural Modeling of Business Objects Generating Smart Glasses-based Information Systems with BPMN4SGA: A BPMN Extension for Smart Glasses Applications Using Blockchain in Peer-to-Peer Carsharing to Build Trust in the Sharing Economy Testing in Big Data: An Architecture Pattern for a Development Environment for Innovative, Integrated and Robust Applications Track 4: Lern- und Wissensmanagement (e-Learning and Knowledge Management) eGovernment Competences revisited – A Literature Review on necessary Competences in a Digitalized Public Sector Say Hello to Your New Automated Tutor – A Structured Literature Review on Pedagogical Conversational Agents Teaching the Digital Transformation of Business Processes: Design of a Simulation Game for Information Systems Education Conceptualizing Immersion for Individual Learning in Virtual Reality Designing a Flipped Classroom Course – a Process Model The Influence of Risk-Taking on Knowledge Exchange and Combination Gamified Feedback durch Avatare im Mobile Learning Alexa, Can You Help Me Solve That Problem? - Understanding the Value of Smart Personal Assistants as Tutors for Complex Problem Tasks Track 5: Data Science & Business Analytics Matching with Bundle Preferences: Tradeoff between Fairness and Truthfulness Applied image recognition: guidelines for using deep learning models in practice Yield Prognosis for the Agrarian Management of Vineyards using Deep Learning for Object Counting Reading Between the Lines of Qualitative Data – How to Detect Hidden Structure Based on Codes Online Auctions with Dual-Threshold Algorithms: An Experimental Study and Practical Evaluation Design Features of Non-Financial Reward Programs for Online Reviews: Evaluation based on Google Maps Data Topic Embeddings – A New Approach to Classify Very Short Documents Based on Predefined Topics Leveraging Unstructured Image Data for Product Quality Improvement Decision Support for Real Estate Investors: Improving Real Estate Valuation with 3D City Models and Points of Interest Knowledge Discovery from CVs: A Topic Modeling Procedure Online Product Descriptions – Boost for your Sales? Entscheidungsunterstützung durch historienbasierte Dienstreihenfolgeplanung mit Pattern A Semi-Automated Approach for Generating Online Review Templates Machine Learning goes Measure Management: Leveraging Anomaly Detection and Parts Search to Improve Product-Cost Optimization Bedeutung von Predictive Analytics für den theoretischen Erkenntnisgewinn in der IS-Forschung Track 6: Digitale Transformation und Dienstleistungen Heuristic Theorizing in Software Development: Deriving Design Principles for Smart Glasses-based Systems Mirroring E-service for Brick and Mortar Retail: An Assessment and Survey Taxonomy of Digital Platforms: A Platform Architecture Perspective Value of Star Players in the Digital Age Local Shopping Platforms – Harnessing Locational Advantages for the Digital Transformation of Local Retail Outlets: A Content Analysis A Socio-Technical Approach to Manage Analytics-as-a-Service – Results of an Action Design Research Project Characterizing Approaches to Digital Transformation: Development of a Taxonomy of Digital Units Expectations vs. Reality – Benefits of Smart Services in the Field of Tension between Industry and Science Innovation Networks and Digital Innovation: How Organizations Use Innovation Networks in a Digitized Environment Characterising Social Reading Platforms— A Taxonomy-Based Approach to Structure the Field Less Complex than Expected – What Really Drives IT Consulting Value Modularity Canvas – A Framework for Visualizing Potentials of Service Modularity Towards a Conceptualization of Capabilities for Innovating Business Models in the Industrial Internet of Things A Taxonomy of Barriers to Digital Transformation Ambidexterity in Service Innovation Research: A Systematic Literature Review Design and success factors of an online solution for cross-pillar pension information Track 7: IT-Management und -Strategie A Frugal Support Structure for New Software Implementations in SMEs How to Structure a Company-wide Adoption of Big Data Analytics The Changing Roles of Innovation Actors and Organizational Antecedents in the Digital Age Bewertung des Kundennutzens von Chatbots für den Einsatz im Servicedesk Understanding the Benefits of Agile Software Development in Regulated Environments Are Employees Following the Rules? On the Effectiveness of IT Consumerization Policies Agile and Attached: The Impact of Agile Practices on Agile Team Members’ Affective Organisational Commitment The Complexity Trap – Limits of IT Flexibility for Supporting Organizational Agility in Decentralized Organizations Platform Openness: A Systematic Literature Review and Avenues for Future Research Competence, Fashion and the Case of Blockchain The Digital Platform Otto.de: A Case Study of Growth, Complexity, and Generativity Track 8: eHealth & alternde Gesellschaft Security and Privacy of Personal Health Records in Cloud Computing Environments – An Experimental Exploration of the Impact of Storage Solutions and Data Breaches Patientenintegration durch Pfadsysteme Digitalisierung in der Stressprävention – eine qualitative Interviewstudie zu Nutzenpotenzialen User Dynamics in Mental Health Forums – A Sentiment Analysis Perspective Intent and the Use of Wearables in the Workplace – A Model Development Understanding Patient Pathways in the Context of Integrated Health Care Services - Implications from a Scoping Review Understanding the Habitual Use of Wearable Activity Trackers On the Fit in Fitness Apps: Studying the Interaction of Motivational Affordances and Users’ Goal Orientations in Affecting the Benefits Gained Gamification in Health Behavior Change Support Systems - A Synthesis of Unintended Side Effects Investigating the Influence of Information Incongruity on Trust-Relations within Trilateral Healthcare Settings Track 9: Krisen- und Kontinuitätsmanagement Potentiale von IKT beim Ausfall kritischer Infrastrukturen: Erwartungen, Informationsgewinnung und Mediennutzung der Zivilbevölkerung in Deutschland Fake News Perception in Germany: A Representative Study of People’s Attitudes and Approaches to Counteract Disinformation Analyzing the Potential of Graphical Building Information for Fire Emergency Responses: Findings from a Controlled Experiment Track 10: Human-Computer Interaction Towards a Taxonomy of Platforms for Conversational Agent Design Measuring Service Encounter Satisfaction with Customer Service Chatbots using Sentiment Analysis Self-Tracking and Gamification: Analyzing the Interplay of Motivations, Usage and Motivation Fulfillment Erfolgsfaktoren von Augmented-Reality-Applikationen: Analyse von Nutzerrezensionen mit dem Review-Mining-Verfahren Designing Dynamic Decision Support for Electronic Requirements Negotiations Who is Stressed by Using ICTs? A Qualitative Comparison Analysis with the Big Five Personality Traits to Understand Technostress Walking the Middle Path: How Medium Trade-Off Exposure Leads to Higher Consumer Satisfaction in Recommender Agents Theory-Based Affordances of Utilitarian, Hedonic and Dual-Purposed Technologies: A Literature Review Eliciting Customer Preferences for Shopping Companion Apps: A Service Quality Approach The Role of Early User Participation in Discovering Software – A Case Study from the Context of Smart Glasses The Fluidity of the Self-Concept as a Framework to Explain the Motivation to Play Video Games Heart over Heels? An Empirical Analysis of the Relationship between Emotions and Review Helpfulness for Experience and Credence Goods Track 11: Information Security and Information Privacy Unfolding Concerns about Augmented Reality Technologies: A Qualitative Analysis of User Perceptions To (Psychologically) Own Data is to Protect Data: How Psychological Ownership Determines Protective Behavior in a Work and Private Context Understanding Data Protection Regulations from a Data Management Perspective: A Capability-Based Approach to EU-GDPR On the Difficulties of Incentivizing Online Privacy through Transparency: A Qualitative Survey of the German Health Insurance Market What is Your Selfie Worth? A Field Study on Individuals’ Valuation of Personal Data Justification of Mass Surveillance: A Quantitative Study An Exploratory Study of Risk Perception for Data Disclosure to a Network of Firms Track 12: Umweltinformatik und nachhaltiges Wirtschaften Kommunikationsfäden im Nadelöhr – Fachliche Prozessmodellierung der Nachhaltigkeitskommunikation am Kapitalmarkt Potentiale und Herausforderungen der Materialflusskostenrechnung Computing Incentives for User-Based Relocation in Carsharing Sustainability’s Coming Home: Preliminary Design Principles for the Sustainable Smart District Substitution of hazardous chemical substances using Deep Learning and t-SNE A Hierarchy of DSMLs in Support of Product Life-Cycle Assessment A Survey of Smart Energy Services for Private Households Door-to-Door Mobility Integrators as Keystone Organizations of Smart Ecosystems: Resources and Value Co-Creation – A Literature Review Ein Entscheidungsunterstützungssystem zur ökonomischen Bewertung von Mieterstrom auf Basis der Clusteranalyse Discovering Blockchain for Sustainable Product-Service Systems to enhance the Circular Economy Digitale Rückverfolgbarkeit von Lebensmitteln: Eine verbraucherinformatische Studie Umweltbewusstsein durch audiovisuelles Content Marketing? Eine experimentelle Untersuchung zur Konsumentenbewertung nachhaltiger Smartphones Towards Predictive Energy Management in Information Systems: A Research Proposal A Web Browser-Based Application for Processing and Analyzing Material Flow Models using the MFCA Methodology Track 13: Digital Work - Social, mobile, smart On Conversational Agents in Information Systems Research: Analyzing the Past to Guide Future Work The Potential of Augmented Reality for Improving Occupational First Aid Prevent a Vicious Circle! The Role of Organizational IT-Capability in Attracting IT-affine Applicants Good, Bad, or Both? Conceptualization and Measurement of Ambivalent User Attitudes Towards AI A Case Study on Cross-Hierarchical Communication in Digital Work Environments ‘Show Me Your People Skills’ - Employing CEO Branding for Corporate Reputation Management in Social Media A Multiorganisational Study of the Drivers and Barriers of Enterprise Collaboration Systems-Enabled Change The More the Merrier? The Effect of Size of Core Team Subgroups on Success of Open Source Projects The Impact of Anthropomorphic and Functional Chatbot Design Features in Enterprise Collaboration Systems on User Acceptance Digital Feedback for Digital Work? Affordances and Constraints of a Feedback App at InsurCorp The Effect of Marker-less Augmented Reality on Task and Learning Performance Antecedents for Cyberloafing – A Literature Review Internal Crowd Work as a Source of Empowerment - An Empirical Analysis of the Perception of Employees in a Crowdtesting Project Track 14: Geschäftsmodelle und digitales Unternehmertum Dividing the ICO Jungle: Extracting and Evaluating Design Archetypes Capturing Value from Data: Exploring Factors Influencing Revenue Model Design for Data-Driven Services Understanding the Role of Data for Innovating Business Models: A System Dynamics Perspective Business Model Innovation and Stakeholder: Exploring Mechanisms and Outcomes of Value Creation and Destruction Business Models for Internet of Things Platforms: Empirical Development of a Taxonomy and Archetypes Revitalizing established Industrial Companies: State of the Art and Success Principles of Digital Corporate Incubators When 1+1 is Greater than 2: Concurrence of Additional Digital and Established Business Models within Companies Special Track 1: Student Track Investigating Personalized Price Discrimination of Textile-, Electronics- and General Stores in German Online Retail From Facets to a Universal Definition – An Analysis of IoT Usage in Retail Is the Technostress Creators Inventory Still an Up-To-Date Measurement Instrument? Results of a Large-Scale Interview Study Application of Media Synchronicity Theory to Creative Tasks in Virtual Teams Using the Example of Design Thinking TrustyTweet: An Indicator-based Browser-Plugin to Assist Users in Dealing with Fake News on Twitter Application of Process Mining Techniques to Support Maintenance-Related Objectives How Voice Can Change Customer Satisfaction: A Comparative Analysis between E-Commerce and Voice Commerce Business Process Compliance and Blockchain: How Does the Ethereum Blockchain Address Challenges of Business Process Compliance? Improving Business Model Configuration through a Question-based Approach The Influence of Situational Factors and Gamification on Intrinsic Motivation and Learning Evaluation von ITSM-Tools für Integration und Management von Cloud-Diensten am Beispiel von ServiceNow How Software Promotes the Integration of Sustainability in Business Process Management Criteria Catalog for Industrial IoT Platforms from the Perspective of the Machine Tool Industry Special Track 3: Demos & Prototyping Privacy-friendly User Location Tracking with Smart Devices: The BeaT Prototype Application-oriented robotics in nursing homes Augmented Reality for Set-up Processe Mixed Reality for supporting Remote-Meetings Gamification zur Motivationssteigerung von Werkern bei der Betriebsdatenerfassung Automatically Extracting and Analyzing Customer Needs from Twitter: A “Needmining” Prototype GaNEsHA: Opportunities for Sustainable Transportation in Smart Cities TUCANA: A platform for using local processing power of edge devices for building data-driven services Demonstrator zur Beschreibung und Visualisierung einer kritischen Infrastruktur Entwicklung einer alltagsnahen persuasiven App zur Bewegungsmotivation für ältere Nutzerinnen und Nutzer A browser-based modeling tool for studying the learning of conceptual modeling based on a multi-modal data collection approach Exergames & Dementia: An interactive System for People with Dementia and their Care-Network Workshops Workshop Ethics and Morality in Business Informatics (Workshop Ethik und Moral in der Wirtschaftsinformatik – EMoWI’19) Model-Based Compliance in Information Systems - Foundations, Case Description and Data Set of the MobIS-Challenge for Students and Doctoral Candidates Report of the Workshop on Concepts and Methods of Identifying Digital Potentials in Information Management Control of Systemic Risks in Global Networks - A Grand Challenge to Information Systems Research Die Mitarbeiter von morgen - Kompetenzen künftiger Mitarbeiter im Bereich Business Analytics Digitaler Konsum: Herausforderungen und Chancen der Verbraucherinformati

Xenograft derived from pediatric tumors, analysis model for tumor cells and tumoral microenvironment

La recherche en cancérologie pédiatrique fait face à de nombreux défis communs aux cancers de l’adulte, mais aussi spécifiques aux populations jeunes. Comme chez l’adulte, l’évaluation de nouvelles thérapies en cancérologie nécessite le développement de modèles de plus en plus sophistiqués qui récapitulent au mieux le développement des cellules tumorales et de leur microenvironnement. Depuis quelques années, les modèles murins xénogreffés avec des tumeurs de patient sont devenus incontournables et viennent compléter un attirail de modèle ex vivo (sphéroïdes, organoïdes, tumoroïdes). Par ailleurs, en cancérologie pédiatrique, ces modèles PDX, en produisant du matériel frais viennent pallier à la rareté de ces pathologies et donc à l’accès à des échantillons pour étudier les mécanismes d’oncogenèse, de résistance aux traitements et de dissémination métastatique. Ces modèles sont d’ores et déja utilisés dans des études en cancérologie mais la présence de séquences humaines (cellules tumorales greffées) et de séquences murines (microenvironnement de l’hôte) induit une complexité qui limite les analyses bioinformatiques. Les objectifs de mes travaux de thèse présentés ici sont, la mise en place d’une méthode de comparaison des profils transcriptomiques de PDX et de patient et l’évaluation de deux cohortes profondes avec des échantillons humains et les PDX associés. PDXploR est la méthode développée lors de ce travail. Cette méthode utilise l’origine différente des séquences des PDX, associé à des méthodes d’analyse en composante principale et d’analyse différentielle, pour comparer séparément les profils d’expression des cellules tumorales et du microenvironnement entre patients et xénogreffes. J’ai appliqué cette méthode pour analyser les cohortes OS2006 PDX et MAPPYACTPS PDX. La première, est composée de 8 modèles d’ostéosarcome avec des échantillons au diagnostic, à la rechute et des PDX sous-cutané et paratibiaux. La seconde, comprend 24 modèles de multiples cancers pédiatriques avec des échantillons à la rechute et des PDX en sous- cutanée. À travers l’étude de ces deux cohortes, nous démontrons la conservation des caractéristiques des tumeurs de patient dans les PDX et montrons que PDXploR permet d’étudier séparement le profil transcriptomique des cellules tumorales et du microenvironnement tumoral. Au-delà de la comparaison d’échantillons de patients et de PDX associés, PDXploR peut être étendu à la comparaison des effets des traitements sur les profils d’expression des cellules tumorales et du microenvironnement.Research in pediatric cancerology is facing many challenges. Some common with adult cancerology, some specific to young population. Like for the adults, the evaluation of new therapies needs the development of sophisticated models reproducing tumoral cell and microenvironment development. For a few years now, the patient derived xenograft model (PDX) became essential in the understanding of cancers. Also, in pediatric cancerology, by producing fresh samples, the PDX models partially resolve the problem related to the rarity of the samples and there acces to study the mechanisms of oncogenesis, treatment resistance and metastatic dissemination. Those models already have been used in cancerology. One major difficulty was identified in those studies, the comparison of transcriptomic profiles from patients to those coming from PDX samples. In the PDX, the profiles are a mix of human sequences (human tumoral cells) and mouse sequences (mouse microenvironment). This duality brings an extra difficulty.The objectivs of the presented work are, the establishment of a comparoison method for the transcriptomic profiles of PDX and corresponding patients samples and, the evaluation of two deep cohorts of pediatric cancers. PDXploR is the method developed in this work.Using the difference in nature of the sequences, principal component analysis and differential expression method, this tool alows to compare PDX and patient samples and to separately analyse the tumor cells and the microenvironment. This method will be used to analyse the cohorts OS2006PDX and MAPPYACTPDX. The first one is composed by 8 osteosarcoma models with samples at Diagnostic, relapse and two xenograft (subcutaneous and paratibial). The second one, is composed by 24 models from various pathology, with samples at the relapse and one subcutaneous xenograft.Through the study of those two cohorts, we demonstrate here the reproductibility of the tumors characteristics in the PDX and that PDXploR alows the study of RNA-seq profiles and separate the tumoral and microenvironmental profiles. Beyond the comparison of patient and PDX samples, PDXploR can be developed to compare the effects of treatments on the expression profiles of the tumors and the microenvironments

Les xénogreffes dérivées de tumeurs pédiatriques, modèles d'analyse des cellules et du microenvironnement tumoral

Research in pediatric cancerology is facing many challenges. Some common with adult cancerology, some specific to young population. Like for the adults, the evaluation of new therapies needs the development of sophisticated models reproducing tumoral cell and microenvironment development. For a few years now, the patient derived xenograft model (PDX) became essential in the understanding of cancers. Also, in pediatric cancerology, by producing fresh samples, the PDX models partially resolve the problem related to the rarity of the samples and there acces to study the mechanisms of oncogenesis, treatment resistance and metastatic dissemination. Those models already have been used in cancerology. One major difficulty was identified in those studies, the comparison of transcriptomic profiles from patients to those coming from PDX samples. In the PDX, the profiles are a mix of human sequences (human tumoral cells) and mouse sequences (mouse microenvironment). This duality brings an extra difficulty.The objectivs of the presented work are, the establishment of a comparoison method for the transcriptomic profiles of PDX and corresponding patients samples and, the evaluation of two deep cohorts of pediatric cancers. PDXploR is the method developed in this work.Using the difference in nature of the sequences, principal component analysis and differential expression method, this tool alows to compare PDX and patient samples and to separately analyse the tumor cells and the microenvironment. This method will be used to analyse the cohorts OS2006PDX and MAPPYACTPDX. The first one is composed by 8 osteosarcoma models with samples at Diagnostic, relapse and two xenograft (subcutaneous and paratibial). The second one, is composed by 24 models from various pathology, with samples at the relapse and one subcutaneous xenograft.Through the study of those two cohorts, we demonstrate here the reproductibility of the tumors characteristics in the PDX and that PDXploR alows the study of RNA-seq profiles and separate the tumoral and microenvironmental profiles. Beyond the comparison of patient and PDX samples, PDXploR can be developed to compare the effects of treatments on the expression profiles of the tumors and the microenvironments.La recherche en cancérologie pédiatrique fait face à de nombreux défis communs aux cancers de l’adulte, mais aussi spécifiques aux populations jeunes. Comme chez l’adulte, l’évaluation de nouvelles thérapies en cancérologie nécessite le développement de modèles de plus en plus sophistiqués qui récapitulent au mieux le développement des cellules tumorales et de leur microenvironnement. Depuis quelques années, les modèles murins xénogreffés avec des tumeurs de patient sont devenus incontournables et viennent compléter un attirail de modèle ex vivo (sphéroïdes, organoïdes, tumoroïdes). Par ailleurs, en cancérologie pédiatrique, ces modèles PDX, en produisant du matériel frais viennent pallier à la rareté de ces pathologies et donc à l’accès à des échantillons pour étudier les mécanismes d’oncogenèse, de résistance aux traitements et de dissémination métastatique. Ces modèles sont d’ores et déja utilisés dans des études en cancérologie mais la présence de séquences humaines (cellules tumorales greffées) et de séquences murines (microenvironnement de l’hôte) induit une complexité qui limite les analyses bioinformatiques. Les objectifs de mes travaux de thèse présentés ici sont, la mise en place d’une méthode de comparaison des profils transcriptomiques de PDX et de patient et l’évaluation de deux cohortes profondes avec des échantillons humains et les PDX associés. PDXploR est la méthode développée lors de ce travail. Cette méthode utilise l’origine différente des séquences des PDX, associé à des méthodes d’analyse en composante principale et d’analyse différentielle, pour comparer séparément les profils d’expression des cellules tumorales et du microenvironnement entre patients et xénogreffes. J’ai appliqué cette méthode pour analyser les cohortes OS2006 PDX et MAPPYACTPS PDX. La première, est composée de 8 modèles d’ostéosarcome avec des échantillons au diagnostic, à la rechute et des PDX sous-cutané et paratibiaux. La seconde, comprend 24 modèles de multiples cancers pédiatriques avec des échantillons à la rechute et des PDX en sous- cutanée. À travers l’étude de ces deux cohortes, nous démontrons la conservation des caractéristiques des tumeurs de patient dans les PDX et montrons que PDXploR permet d’étudier séparement le profil transcriptomique des cellules tumorales et du microenvironnement tumoral. Au-delà de la comparaison d’échantillons de patients et de PDX associés, PDXploR peut être étendu à la comparaison des effets des traitements sur les profils d’expression des cellules tumorales et du microenvironnement

Recent advances in understanding osteosarcoma and emerging therapies

International audienceOsteosarcoma is the most common bone cancer in adolescents and young adults, but it is a rare cancer with no improvement in patient survival in the last four decades. The main problem of this bone tumor is its evolution toward lung metastatic disease, despite the current treatment strategy (chemotherapy and surgery). To further improve survival, there is a strong need for new therapies that control osteosarcoma cells with metastatic potential and their favoring tumor microenvironment (ME) from the diagnosis. However, the complexity and heterogeneity of those tumor cell genomic/epigenetic and biology, the diversity of tumor ME where it develops, the sparsity of appropriate preclinical models, and the heterogeneity of therapeutic trials have rendered the task difficult. No tumor- or ME-targeted drugs are routinely available in front-line treatment. This article presents up-to-date information from preclinical and clinical studies that were recently published or presented in recent meetings which we hope might help change the osteosarcoma treatment landscape and patient survival in the near future

A biobank of pediatric patient-derived-xenograft models in cancer precision medicine trial MAPPYACTS for relapsed and refractory tumors

Abstract Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies