http://hdl.handle.net/10993/107 Search this channel search https://orbilu.uni.lu/simple-search http://hdl.handle.net/10993/55825 Title: STUDY OF EARLY MELANOMA BRAIN METASTASIS MECHANISMS USING IN VITRO AND IN VIVO MODELS OF TUMOR INVASION <br/> <br/>Author, co-author: Slimani, Rédouane <br/> <br/>Abstract: Of all skin cancers, melanoma is the most fatal. Of all cancer types, melanoma is also the cancer with the highest level of brain tropism. Approximately 50% of patients with stage IV melanoma are diagnosed with melanoma brain metastases. A percentage that rises when postmortem patients are also taken into account. Following lung cancer and breast cancer, melanoma is the leading cause of malignant metastasis to the central nervous system. Of all metastatic brain tumors, melanoma represents 6-12% of cases. The overall survival rate following a diagnosis of melanoma brain metastases has been historically low. However, over the past ten years, advances in targeted therapies as well as in immunotherapies have significantly improved the survival rate of patients with advanced melanoma. Melanoma brain metastases most frequently occur at the junction between the gray and the white matter and in the frontal lobe. In order to reach the brain parenchyma, metastases must cross the brain vasculature. The specific properties of the blood vessels that perfuse the central nervous system are referred to as the blood-brain barrier. They allow these vessels to finely regulate the flow of cells, ions and molecules between the bloodstream and the brain parenchyma in order to preserve brain homeostasis for the proper functioning of neurons and the protection of the brain against toxic and pathogenic agents. Abnormalities in this functional interfacing barrier that separates the brain from the bloodstream are a critical element in the development and progression of several neurological pathologies. A poor understanding of the early mechanisms of metastasis crossing the blood-brain barrier constitutes an obstacle to the development of effective preventive therapeutic strategies as well as a particularly challenging domain of interest as it is one of the most crucial and least documented steps in the metastasizing process to the brain. Here, we focused on the ideation and consequent creation of effective in vitro and in vivo models to help identify and characterize as meticulously as possible, the players that are implicated in the crossing of melanoma metastases through the blood-brain barrier to reach the brain parenchyma. We used human immortalized cells (endothelial cells, pericytes and astrocytes) in triple coculture to recreate a blood-brain barrier in vitro and be able to investigate eventual changes in the gene expression of the tumor cells crossing the model. In parallel, we have set up an in vivo murine model to recreate the process of brain metastasis by injecting melanoma tumor cells into the left ventricle of the heart and thus be able to study the early stages of blood-brain barrier invasion. The analysis of the murine tissues was performed by Correlative light-electron microscopy (CLEM) and the results obtained revealed the presence of cells in the brain that present artifacts that have the same appearance as melanosomes. Experiments using focused ion beam scanning electron microscopes (FIB-SEM) as well as nanoscale secondary ion mass spectrometry (NanoSIMS) may be conducted to take the investigation further. http://hdl.handle.net/10993/54800 Title: Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence <br/> <br/>Author, co-author: Hassanin, Emadeldin Saeed Fathy Sayed; Spier, Isabel; Bobbili, Dheeraj Reddy; Aldisi, Rana; Klinkhammer, Hannah; David, Friederike; Dueñas, Nuria; Hüneburg, Robert; Perne, Claudia; Brunet, Joan; Capella, Gabriel; Nöthen, Markus M.; Forstner, Andreas J.; Mayr, Andreas; Krawitz, Peter; May, Patrick; Aretz, Stefan; Maj, Carlo <br/> <br/>Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes ( APC, MLH1, MSH2, MSH6, PMS2) , 2. low (\textless 20\%), intermediate (20–80\%), or high PRS (\textgreater 80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups. http://hdl.handle.net/10993/54772 Title: Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation <br/> <br/>Author, co-author: Nedara, Kenza; Reinhardt, Camille; Lebraud, Emilie; Arena, Giuseppe; Gracia, Céline; Buard, Valérie; Pioche-Durieu, Catherine; Castelli, Florence; Colsch, Benoit; Bénit, Paule; Rustin, Pierre; Albaud, Benoit; Gestraud, Pierre; Baulande, Sylvain; Servant, Nicolas; Deutsch, Eric; Verbavatz, Jean-Marc; Brenner, Catherine; Milliat, Fabien; Modjtahedi, Nazanine <br/> <br/>Abstract: Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine. Although recent reports indicate that TRIAP1 is a prosurvival factor abnormally overexpressed in various types of cancer, knowledge about its molecular and metabolic function in human cells is still elusive. It is therefore critical to understand the metabolic and proliferative advantages that TRIAP1 expression provides to cancer cells. Here, in a colorectal cancer cell model, we report that the expression of TRIAP1 supports cancer cell proliferation and tumorigenesis. Depletion of TRIAP1 perturbed the mitochondrial ultrastructure, without a major impact on CL levels and mitochondrial activity. TRIAP1 depletion caused extramitochondrial perturbations resulting in changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. Furthermore, we observed that TRIAP1 depletion conferred a robust p53-mediated resistance to the metabolic stress caused by glutamine deprivation. These findings highlight the importance of TRIAP1 in tumorigenesis and indicate that the loss of TRIAP1 has extramitochondrial consequences that could impact on the metabolic plasticity of cancer cells and their response to conditions of nutrient deprivation. http://hdl.handle.net/10993/54426 Title: Improving neuroblastoma therapy by targeting intra-tumoral hypoxia and immune checkpoint axis PD-1/PD-L1 <br/> <br/>Author, co-author: Sauvage, Delphine http://hdl.handle.net/10993/53968 Title: MiRNAs from serum-derived extracellular vesicles as biomarkers for uveal melanoma progression <br/> <br/>Author, co-author: Wroblewska, Joanna Patrycja; Lach, Michał Stefan; Rucinski, Marcin; Piotrowski, Igor; Galus, Lukasz; Suchorska, Wiktoria Maria; Kreis, Stephanie; Marszałek, Andrzej <br/> <br/>Abstract: Uveal melanoma (UM) is a rare type of malignancy that originates from melanocytes located in the choroid, iris and the ciliary body of the eye. UM has a very high mortality upon metastatic spread to the liver, the prime target organ for UM metastasis. The lack of effective therapies for advanced stages of the disease aggravate the prognosis further. Moreover, biomarkers for early detection and progression of UM, especially the molecular traits governing the development of metastasis, are still not available in clinical practice. One extensively studied components of liquid biopsies are exosomes, a subtype of extracellular vesicle. Due to their unique molecular cargo, they could be used as carriers of early markers of cancer development and progression. For characterisation of the miRNA profiles present in circulating serum-derived exosomes of patients with diagnosed primary and metastatic UM, we have analysed the miRNA cargos using next-generation sequencing followed by RT-qPCR validation in a cohort of patients (control n=20; primary n=9; metastatic n=11). Nine miRNAs clearly differentiating these patient groups have been established. We show that hsa-miR-223 and hsa-miR-203a are the most promising biomarker candidates, allowing categorization of patients into local and advanced UM. Additionally, the comparison of miRNA expression levels in exosomes derived from UM patients with those derived from healthy donors, revealed that hsa-miR-144 has the potential to be used as an early marker for presence of UM. Taken together, this pilot study reveals that miRNAs extracted from circulating exosomes could be exploited as potential biomarkers in UM diagnosis and, more importantly, for indicating metastatic spread. http://hdl.handle.net/10993/52154 Title: SYSTEMS METHODS FOR ANALYSIS OF HETEROGENEOUS GLIOBLASTOMA DATASETS TOWARDS ELUCIDATION OF INTER-TUMOURAL RESISTANCE PATHWAYS AND NEW THERAPEUTIC TARGETS <br/> <br/>Author, co-author: Tching Chi Yen, Romain Mana Hiao Woun <br/> <br/>Abstract: In this PhD thesis is described an endeavour to compile litterature about Glioblastoma key molecular mechanisms into a directed network followin Disease Maps standards, analyse its topology and compare results with quantitative analysis of multi-omics datasets in order to investigate Glioblastoma resistance mechanisms. The work also integrated implementation of Data Management good practices and procedures. <br/> <br/>Commentary: This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 766069. http://hdl.handle.net/10993/50410 Title: Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence 2022.01.20.22269585 <br/> <br/>Author, co-author: Hassanin, Emadeldin; Spier, Isabel; Bobbili, Dheeraj Reddy; Aldisi, Rana; Klinkhammer, Hannah; David, Friederike; Dueñas, Nuria; Hüneburg, Robert; Perne, Claudia; Brunet, Joan; Capella, Gabriel; Nöthen, Markus M.; Forstner, Andreas J.; Mayr, Andreas; Krawitz, Peter; May, Patrick; Aretz, Stefan; Maj, Carlo <br/> <br/>Abstract: Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification.Methods To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (<20%), intermediate (20-80%), or high PRS (>80\%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22\%, compared to 40 and 74 for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26 for non-carriers and 98 for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups. http://hdl.handle.net/10993/48881 Title: Intraoperative discrimination of native meningioma and dura mater by Raman spectroscopy <br/> <br/>Author, co-author: Jelke, Finn; Mirizzi, Giulia; Borgmann, Felix Kleine; Husch, Andreas; Slimani, Rédouane; Klamminger, Gilbert Georg; Klein, Karoline; Mombaerts, Laurent; Gerardy, Jean-Jacques; Mittelbronn, Michel; Hertel, Frank <br/> <br/>Commentary: 0123456789 http://hdl.handle.net/10993/48785 Title: Breast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history <br/> <br/>Author, co-author: Hassanin, Emadeldin; May, Patrick; Aldisi, Rana; Spier, Isabel; Forstner, Andreas J.; Nöthen, Markus M.; Aretz, Stefan; Krawitz, Peter; Bobbili, Dheeraj Reddy; Maj, Carlo <br/> <br/>Abstract: Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification. http://hdl.handle.net/10993/48649 Title: Differentiation of primary CNS lymphoma and glioblastoma using Raman spectroscopy and machine learning algorithms <br/> <br/>Author, co-author: Klamminger, Gilbert Georg; Klein, Karoline; Mombaerts, Laurent; Jelke, Finn; Mirizzi, Giulia; Slimani, Rédouane; Husch, Andreas; Mittelbronn, Michel; Hertel, Frank; Borgmann, Felix Bruno Kleine <br/> <br/>Abstract: Objective and Methods: Timely discrimination between primary CNS lymphoma (PCNSL) and glioblastoma is crucial for diagnostics and therapy, but most importantly also determines the intraoperative surgical course. Advanced radiological methods allow this to a certain extent but ultimately, biopsy is still necessary for final diagnosis. As an upcoming method that enables tissue analysis by tracking changes in the vibrational state of molecules via inelastic scattered photons, we used Raman Spectroscopy (RS) as a label free method to examine specimens of both tumor entities intraoperatively, as well as postoperatively in formalin fixed paraffin embedded (FFPE) samples. Results: We applied and compared statistical performance of linear and nonlinear machine learning algorithms (Logistic Regression, Random Forest and XGBoost), and found that Random Forest classification distinguished the two tumor entities with a balanced accuracy of 82,4% in intraoperative tissue condition and with 94% using measurements of distinct tumor areas on FFPE tissue. Taking a deeper insight into the spectral properties of the tumor entities, we describe different tumor-specific Raman shifts of interest for classification. Conclusions: Due to our findings, we propose RS as an additional tool for fast and non-destructive, perioperative tumor tissue discrimination, which may augment treatment options at an early stage. RS may further serve as a useful additional tool for neuropathological diagnostics with little requirements for tissue integrity. http://hdl.handle.net/10993/47737 Title: Functional Analysis of Long Noncoding RNAs in Glioblastoma and Chemoresistance <br/> <br/>Author, co-author: Sarmini, Mohamad http://hdl.handle.net/10993/47448 Title: Assessing the role of polygenic background on the penetrance of monogenic forms in Parkinson\textquoterights disease. 2021.06.06.21253270 <br/> <br/>Author, co-author: Hassanin, Emadeldin; May, Patrick; Aldisi, Rana; Krawitz, Peter; Maj, Carlo; Bobbili, Dheeraj Reddy <br/> <br/>Abstract: Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinson's disease among carriers of rare monogenic variants in known Parkinson's disease genes and those with a family history. Methods: We calculated the PRS based on common variants and selected the carriers of rare monogenic variants by using the exome data from UK Biobank. Individuals were divided into three risk categories based on PRS: low (<10%), intermediate (10%-90%), and high (>90%) risk groups. We then compared how PRS affects Parkinson\textquoterights disease risk among carriers of rare monogenic variants and those with family-history. Results: We observed a two-fold higher odds ratio for a carrier of a monogenic variant that had a high PRS (OR 4.07,95\% CI, 1.72-8.08) compared to carriers with a low PRS (OR 1.91, 95\% CI, 0.31-6.05). In the same line, carriers with a first-degree family history and with \>90\% PRS have even a higher risk of developing PD (OR 23.53, 95\%CI 5.39-71.54) compared to those with \<90\% PRS (OR 9.54, 95\% CI 3.32-21.65). Conclusions: Our results show that PRS, carrier status, and family history contribute independently and additively to the Parkinson's disease risk. http://hdl.handle.net/10993/47405 Title: Identifying and targeting metabolic vulnerabilities of IDH mutant gliomas <br/> <br/>Author, co-author: Cano Galiano, Andrés <br/> <br/>Abstract: Diffuse gliomas are a group of central nervous system (CNS) tumors with a poor patient prognosis. Within these diffuse gliomas, isocitrate dehydrogenase (IDH) mutation defines the different tumor subtypes and is considered to be an initiating event in gliomagenesis. IDH is a metabolic enzyme that in normal conditions mediates the conversion of isocitrate into α-ketoglutarate (α-KG), producing the reducing equivalent NADPH. IDH mutation (IDHm) leads to a neomorphic reaction where α-KG is consumed to generate the oncometabolite D-2-hydroxyglutarate (D-2HG), using NADPH as reducing agent. It has been reported that IDHm-dependent D-2HG synthesis has a direct impact on DNA and histone methylation, however the metabolic repercussions are not yet well defined. Due to the consumption of NADPH by IDHm reaction, some groups including us have hypothesized that IDHm cells may bear an imbalance of reducing equivalents, that may trigger a defective antioxidant defense. In the present study we made use of patient-derived cell lines and xenografts thereof as well as clinical samples in order to study the metabolic vulnerabilities of IDHm gliomas. In the first part of the thesis experimental data, we generated an integrative liquid chromatography-mass spectrometry (LCMS)-based proteomic-metabolomic characterization of IDHm metabolism. We made use of patients, cell lines and xenografts to address the direct effect of the mutation. We observed that IDHm gliomas have altered regulation of key processes in central carbon metabolism through glucose and glutamate processing as well as glutathione (GSH) metabolism and fatty acid production. In the second part of experimental data, we investigated the redox vulnerabilities of IDHm gliomas. Here we discovered that IDHm astrocytomas specifically upregulate cystathionine-γ-lyase (CSE) enabling them to synthesize GSH independently of NADPH. CSE is the only known enzyme capable of synthesizing cysteine. We found that genetic and chemical inhibition of CSE led to a decrease in cell viability upon cysteine restriction. Finally inhibition of CSE in vivo led to a delay in tumor growth rate. In conclusion, in the present PhD dissertation we expose a comprehensive study of the metabolic behavior of IDHm human gliomas, and we propose a novel therapeutic strategy that might improve patient prognosis, by inflicting oxidative damage to the tumor. http://hdl.handle.net/10993/46083 Title: Prévention primaire <br/> <br/>Author, co-author: Barré, Jessica; Bejko, Dritan; Bendiane, Marc-Karim; Couffignal, Sophie; Huiart, Laetitia; Samouda, Hanen; Alkerwi, Ala'a; Brochmann, Chantal; Eicher, Carole; Ferreira Da Costa, Marisa; Ziade, Bechara Georges; Goerens, Robert; Harpes, Nico; Lehners, Scharel; Lorcy, Anne-Charlotte; Lorin, Fanny; Marques, Pedro; Papadopoulou, Afroditi; Pier, Karin; Pivot, Diane; Steil, Simone; Weber, Guy; Heinz, Andreas; Willems, Helmut Erich <br/> <br/>Abstract: Le chapitre prévention primaire se concentre sur les facteurs de risques externes établis comme principaux, liés au mode de vie des personnes, à savoir le tabac, l’alcool, l’alimentation, l’activité physique et la surcharge pondérale et l’obésité, susceptibles d’engendrer un cancer. L’éducation à la santé joue un rôle important, afin d’amener les individus à adopter des comportements préventifs, dans l’objectif de prévenir une maladie ou de la détecter à un stade asymptomatique. Les données des enquêtes European Health Interview Survey (EHIS, étude pilotée par le Ministère de la Santé et le Luxembourg Institute of Health) et Health Behaviour in School-Aged Children (HBSC, enquête coordonnée au Luxembourg par le Ministère de la Santé, le Ministère de l’Education nationale, de l’Enfance et de la Jeunesse, et l’Université de Luxembourg) ont été utilisées dans ce chapitre, pour compiler les données statistiques liées aux facteurs de risques. L’ensemble des comparaisons européennes est réalisé par Eurostat, (https://ec.europa.eu/), par l’étude internationale HBSC (http://www.hbsc.org/) et par le réseau international de chercheurs HBSC. Le chapitre se poursuit sur un descriptif des démarches de prévention mises en place sur le territoire national, au regard des facteurs de risques exposés au paragraphe 1, par exemple pour : Le tabac : Plan National de Lutte contre le Tabagisme (PNLT) 2016-2020, programme de sevrage tabagique (Ministère de la Santé/ Caisse Nationale de Santé), loi du 13 juin 2017 transposant la directive européenne 2014/40/UE sur les produits tabac ; L’alcool : Loi du 22 décembre 2006 portant interdiction de la vente de boissons alcoolisées à des mineurs de moins de seize ans, Plan d’Action Luxembourgeois de réduction du Mésusage de l’Alcool (PALMA) 2020-2024 ; L’alimentation et l’activité physique : Plan Cadre National « Gesond Iessen, Mei Bewegen » (PCN GIMB) 2018-2025. D’autres facteurs de risques additionnels ont par ailleurs été identifiés et font l’objet d’une prise en charge spécifique (ex : exposition au radon, recommandations de prescriptions en imagerie médicale, exposition aux UV, vaccination contre le HPV et l’hépatite B, exposition professionnelle à des agents cancérigènes…). Le rôle et les actions de la Direction de la Médecine Préventive de la Direction de la Santé, et de la Fondation Cancer, sont rappelés, dans ce cadre. http://hdl.handle.net/10993/44421 Title: Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology. <br/> <br/>Author, co-author: Golebiewska, Anna; Hau, Ann-Christin; Oudin, Anaïs; Stieber, Daniel; Yabo, Yahaya A.; Baus, Virginie; Barthelemy, Vanessa; Klein, Eliane; Bougnaud, Sébastien; Keunen, Olivier; Wantz, May; Michelucci, Alessandro; Neirinckx, Virginie; Muller, Arnaud; Kaoma, Tony; Nazarov, Petr V.; Azuaje, Francisco; De Falco, Alfonso; Flies, Ben; Richart, Lorraine; Poovathingal, Suresh; Arns, Thais; Grzyb, Kamil; Mock, Andreas; Herold-Mende, Christel; Steino, Anne; Brown, Dennis; May, Patrick; Miletic, Hrvoje; Malta, Tathiane M.; Noushmehr, Houtan; Kwon, Yong-Jun; Jahn, Winnie; Klink, Barbara; Tanner, Georgette; Stead, Lucy F.; Mittelbronn, Michel; Skupin, Alexander; Hertel, Frank; Bjerkvig, Rolf; Niclou, Simone <br/> <br/>Abstract: Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology. http://hdl.handle.net/10993/43569 Title: Evaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients <br/> <br/>Author, co-author: Fehlmann, Tobias; Kahraman, Mustafa; Backes, Christina; Galata, Valentina; Keller, Verena; Geffers, Lars; Mercaldo, Nathaniel; Hornung, Daniela; Keller, Andreas; Krüger, Rejko; Balling, Rudolf <br/> <br/>Abstract: Importance The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular signatures, such as blood-borne microRNA (miRNA) signatures, may have high rates of sensitivity and specificity but require additional studies with large cohorts and standardized measurements to confirm the generalizability of miRNA signatures. Objective To investigate the use of blood-borne miRNAs as potential circulating markers for detecting lung cancer in an extended cohort of symptomatic patients and control participants. Design, Setting, and Participants This multicenter, cohort study included patients from case-control and cohort studies (TREND and COSYCONET) with 3102 patients being enrolled by convenience sampling between March 3, 2009, and March 19, 2018. For the cohort study TREND, population sampling was performed. Clinical diagnoses were obtained for 3046 patients (606 patients with non–small cell and small cell lung cancer, 593 patients with nontumor lung diseases, 883 patients with diseases not affecting the lung, and 964 unaffected control participants). No samples were removed because of experimental issues. The collected data were analyzed between April 2018 and November 2019. Main Outcomes and Measures Sensitivity and specificity of liquid biopsy using miRNA signatures for detection of lung cancer. Results A total of 3102 patients with a mean (SD) age of 61.1 (16.2) years were enrolled. Data on the sex of the participants were available for 2856 participants; 1727 (60.5%) were men. Genome-wide miRNA profiles of blood samples from 3046 individuals were evaluated by machine-learning methods. Three classification scenarios were investigated by splitting the samples equally into training and validation sets. First, a 15-miRNA signature from the training set was used to distinguish patients diagnosed with lung cancer from all other individuals in the validation set with an accuracy of 91.4% (95% CI, 91.0%-91.9%), a sensitivity of 82.8% (95% CI, 81.5%-84.1%), and a specificity of 93.5% (95% CI, 93.2%-93.8%). Second, a 14-miRNA signature from the training set was used to distinguish patients with lung cancer from patients with nontumor lung diseases in the validation set with an accuracy of 92.5% (95% CI, 92.1%-92.9%), sensitivity of 96.4% (95% CI, 95.9%-96.9%), and specificity of 88.6% (95% CI, 88.1%-89.2%). Third, a 14-miRNA signature from the training set was used to distinguish patients with early-stage lung cancer from all individuals without lung cancer in the validation set with an accuracy of 95.9% (95% CI, 95.7%-96.2%), sensitivity of 76.3% (95% CI, 74.5%-78.0%), and specificity of 97.5% (95% CI, 97.2%-97.7%). Conclusions and Relevance The findings of the study suggest that the identified patterns of miRNAs may be used as a component of a minimally invasive lung cancer test, complementing imaging, sputum cytology, and biopsy tests. http://hdl.handle.net/10993/43022 Title: Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine <br/> <br/>Author, co-author: Golebiewska, Anna; Hau, Ann-Christin; Oudin, Anais; Stieber, Daniel; Yabo, Yahaya A.; Baus, Virginie; Barthelemy, Vanessa; Klein, Eliane; Bougnaud, Sebastien; Keunen, Olivier; Wantz, May; Michelucci, Alessandro; Neirinckx, Virginie; Muller, Arnaud; Kaoma, Tony; Nazarov, Petr V.; Azuaje, Francisco; De Falco, Alfonso; Flies, Ben; Richart, Lorraine; Poovathingal, Suresh; Arns, Thais; Grzyb, Kamil; Mock, Andreas; Herold-Mende, Christel; Steino, Anne; Brown, Dennis; May, Patrick; Miletic, Hrvoje; Malta, Tathiane M.; Noushmehr, Houtan; Kwon, Yong-Jun; Jahn, Winnie; Klink, Barbara; Tanner, Georgette; Stead, Lucy F.; Mittelbronn, Michel; Skupin, Alexander; Hertel, Frank; Bjerkvig, Rolf; Niclou, Simone <br/> <br/>Abstract: Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies. http://hdl.handle.net/10993/42708 Title: Continuous Professional Development: Elevating Thoracic Oncology Education in Europe <br/> <br/>Author, co-author: van Geffen, Wouter H; Blum, Torsten G; Aliberti, Stefano; Blyth, Kevin G; Bostantzoglou, Clementine; Farr, Amy; Grigoriu, Bogdan; Hardavella, Georgia; Huber, Rudolf M; Maskell, Nick; Massard, Gilbert; Rahman, Najib M; Stolz, Daiana; van Meerbeeck, Jan http://hdl.handle.net/10993/40425 Title: Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells <br/> <br/>Author, co-author: Santio, Niina M.; Landor, Sebastian K.-J.; Vahtera, Laura; Yla-Pelto, Jani; Paloniemi, Elina; Imanishi, Susumu Y.; Corthals, Garry; Varjosalo, Markku; Manoharan, Ganesh Babu; Uri, Asko; Lendahl, Urban; Sahlgren, Cecilia; Koskinen, Paivi J. <br/> <br/>Abstract: Tumorigenesis is a multistep process involving co-operation between several deregulated oncoproteins. In this study, we unravel previously unrecognized interactions and crosstalk between Pim kinases and the Notch signaling pathway, with implications for both breast and prostate cancer. We identify Notch1 and Notch3, but not Notch2, as novel Pim substrates and demonstrate that for Notch1, the serine residue 2152 is phosphorylated by all three Pim family kinases. This target site is located in the second nuclear localization sequence (NLS) of the Notch1 intracellular domain (N1ICD), and is shown to be important for both nuclear localization and transcriptional activity of N1ICD. Phosphorylation-dependent stimulation of Notch1 signaling promotes migration of prostate cancer cells, balances glucose metabolism in breast cancer cells, and supports in vivo growth of both types of cancer cells on chick embryo chorioallantoic membranes. Furthermore, Pim-induced growth of orthotopic prostate xenografts in mice is associated with enhanced nuclear Notch1 activity. Finally, simultaneous inhibition of Pim and Notch abrogates the cellular responses more efficiently than individual treatments, opening up new vistas for combinatorial cancer therapy. http://hdl.handle.net/10993/39977 Title: Mathematical Histopathology and Systems Pharmacology of Melanoma <br/> <br/>Author, co-author: Albrecht, Marco <br/> <br/>Abstract: Treated metastatic melanoma often becomes resistant and relapses whereby resistance mechanisms can be found at the level of biochemical, histological, and pharmacological data. By using this data in a mathematical form, an integrative understanding of tumour progression can be gained that reveal the functionality of more complex and hidden recurrence mechanisms. The aims of this thesis were - to investigate how a new engineering concept on tumour growth, based on porous media theory, can be leveraged to support medicine and cancer biology research, - to identify suitable tests for cancer growth model validation, - to study how elements of biochemical cancer pathways are linked to the elements of physical growth, and - to establish a pharmacokinetics module for the melanoma cancer drug dabrafenib. The studied engineering concept is qualitatively suitable to represent late-stage metastatic melanoma in irregular fibrous tissue types, whereby all equations are tested for biological relevance and parametrisation. The framework allows modelling of tissue-specific growth, and the thesis shows that the simulated tumour can shift between compact growth with ECM displacement and invasive growth with ECM circumvention as a consequence of cell plasticity/viscosity change. This is unique among continuous models of tumour growth. However, the investigation also shows that the pressure-saturation relationships are not biologically motivated and can be replaced by a swelling polymer model which captures the water absorbing effect of glycans. The thesis addresses a biologically and computationally reasonable strategy to validate the tumour growth model as complete as possible. A suitable way to validate a part of the tumour growth model is using time course data of spheroid growth in hydrogels of different stiffness values. Spheroids generated from the LU451 melanoma cell line mainly grow due to ECM degradation, have a time-variant growth rate increasing with gel rigidity, and the confined environment renders the melanoma cell line drug-resistant upon dabrafenib dose escalation. This setting reveals the interplay between mechanical and biochemical development over time. The dependency between biological elements of cancer pathways and the mechanical elements of the engineering concept on tumour growth were clarified. Therefore, the literature on mechanoregulation has been reviewed and serves as a computational link between systems biology and physical oncology. Finally, the thesis provides preliminary steps and a concept toward a serious interdisciplinary methodology to understand tumour growth, although this cannot be considered a final model for any of the known melanoma growth settings. Additionally, the thesis provides a novel quantitative systems pharmacology approach to consider liver-enzyme-induction and drug-drug-interaction. The finding is that the potent dabrafenib metabolite desmethyl-dabrafenib accumulates with consequential efficacy loss in a confined tumour environment.