Micro-injection of single bacteria into a gut organoid model has recently been used to reveal the causative role of a genotoxic pks+E.coli mutational signature in CRC. Our team is currently establishing micro-injection of the well described CRC-associated bacteria, Fusobacterium nucleatum (to be extended during the course of the project to complex microbiome communities), into tumour organoid and preliminary data suggest extensive epigenetic remodelling in tumour cells. We will further use this micro-injection-based model to determine chromatin accessibility by single nuclei ATAC-seq upon single or complex microbiota challenge of tumour cells, thereby distinguishing between changes induced by microbiota secretome and direct microbe interactions.
Prof Lasse Sinkkonen holds a PhD in Biochemistry from University of Basel and is currently the Head of the Epigenetics team at the UL Department of Life Sciences and Medicine. His research is focused on understanding the gene regulatory control of cell identity at the level of chromatin in both development and disease. The Epigenetics team applies genome-wide and single cell technologies to reveal the key regulators of cell states and the associated cellular heterogeneity during differentiation and in diseases such as Parkinson’s disease and cancer. A particular focus is placed on the interplay between metabolites and epigenetic control of gene expression in cancer.
The role of host feedback on the microbial community has been largely neglected until now. Our team has developed diverse workflows, which allow to track microbial behaviour using microfluidics, advanced imaging, in-house-robotics, mathematics and machine learning tools. Here we will use these tools and combine physics, mathematical sciences, and biology to understand how biophysical parameters (ECM, rigidity) within the TE regulate the dynamics of the cancer microbiome. The advantage of such models is that the cell-to-cell and cell-to-matrix interactions, which are essential for mimicking accurate physiological conditions and responses, are maintained.
Prof Anupam Sengupta is an FNR ATTRACT Fellow and Head of the Physics of Living Matter group at UL Department of Physics and Materials Science. After obtaining BS-MS degrees in Mechanical Engineering from the IIT Bombay (India), Anupam joined the Max Planck Institute (Göttingen, Germany). In 2013 he received a PhD in Physics for his work on liquid crystal microfluidics. Prof Sengupta was a Human Frontier Cross-Disciplinary Fellow (2014-2017), first at the MIT (USA) and then at ETH Zurich (Switzerland), working on the physical ecology of microbes. Since 2018, he directs a multi-disciplinary team in Luxembourg, combining material physics, microbiology, mathematical modelling and machine learning to understand microbial response and adaptation. He is a member of the UL Institute of Advanced Studies and serves as the Director of the undergraduate physics studies.
Recently, it has become increasingly evident that focus should not only be put on individual bacterial species, but also on the various metabolites that they secrete. The microfluidics HuMiX device, developed at UL, was already used within the consortium to study single bacteria-host interaction with tumour and immune cells. In CANBIO2, it will be adapted and transformed into a cancer-on-a-chip model to study the metabolic cross-talk taking place between complex patient-derived microbiome communities and host cells. The outcome of these projects will lead to the identification of metabolites that can be specifically studied in WP2 (P8, P10).
Prof Paul Wilmes is Professor of Systems Ecology at the UL. As a British Chevening Scholar, Paul earned his PhD from the School of Environmental Sciences at the University of East Anglia (UK). For part of his doctoral research, he spent time as a German Academic Exchange Service Visiting Scientist at the Max Planck Institute for Marine Microbiology in Bremen (Germany). Paul subsequently carried out postdoctoral research at the University of California, Berkeley (USA) from where he returned in 2010 to his native Luxembourg through the FNR ATTRACT fellowship scheme Paul was awarded an European Research Council (ERC) Consolidator Grant in 2019.
Our team has recently established a humanised microbiome model (based on faecal transplantation of human microbiota in germ free mice performed in our recently established germ-free mouse facility). This avatar model will now be further developed and coupled to a colonoscopy-based orthotopic injection of organoids in the colon wall to recapitulate the full metastatic cascade. They will help us determine the role of the microbiota in metastases and identify new strategies to reverse the harmful effects of cancer-associated bacteria. Importantly, these avatar models can be further extended to other tumour types and are at the disposal of all the projects within the consortium to validate microbiome-based targets.
Dr Elisabeth Letellier is co-heading the Molecular Disease Mechanisms group at the UL Department of Life Sciences and Medicine. Her current research activities mainly aim at understanding the mechanisms underlying tumour initiation and progression in colorectal cancer (CRC), with a special focus on the tumour microenvironment (TME). The group has developed state-of-the-art in silico (different bioinformatics tools as well as metabolic modelling), in vitro (3D organoids cultures of patient-derived samples) and in vivo models (CRC models and gnotobiotic mice) to understand how the different cell types of the TME, including immune cells and the cancer-associated fibroblasts as well as the different bacterial species of the gut microbiome, interact with the tumour cells.
A prerequisite for metabolic studies in advanced cancer models, is the adaptation of respective protocols to account for the experimental and analytical challenges that go along with the transition from 2D to complex 3D models. Here, we will translate our robust profiling pipeline to advanced 3D cancer models. Taking advantage of different 3D models available within the consortium, the profiling pipeline will be first benchmarked by validating known metabolic alterations in melanoma, CRC and glioma. Subsequently, metabolic profiling upon TE-relevant constraints (hypoxia and nutrient deprivation) will be applied. This approach may also help to identify novel disease-relevant entry points to counteract drug resistance (P1, 13, 16). In the long run, this pipeline will also be used to create tumour type-specific metabolic maps with the aim to make it available to the cancer research community.
Dr Johannes Meiser is leading the Cancer Metabolism Group at LIH’s Department of Cancer Research. During a successful postdoctoral stay at the Cancer Research UK Beatson Institute, he specialised in the field of cancer metabolism. In 2018, he successfully transitioned to a Principal Investigator position at LIH, core funded by the FNR ATTRACT program. The expertise of the Meiser lab resides at the quantitative analysis of mammalian cell metabolism applying stable isotope-assisted metabolic flux analysis and analytical chemistry using Mass Spectrometry. A particular focus of the group is set but not limited to folate-dependent serine metabolism.
Since the advent of immune-checkpoint blockade, T-cells gained much attention in regard to their anti-cancer properties. It has also become obvious that alterations of the metabolic landscape impact T-cell functionality. Yet, an in-depth understanding of metabolic determinants that control phenotypes is only starting to arise. A recent metabolic screen (unpublished) performed in the Brenner lab has uncovered new regulators that impact the immune response of cytotoxic T-cells. These identified targets will be mechanistically characterised to understand their role in the immunological circuit. In addition to ex vivo T-cell assays, genetically engineered mouse models will be employed.
Prof Dirk Brenner is Deputy Director (Research & Strategy) of the LIH’s Department of Infection and Immunity and Full Professor of Immunology & Genetics at the Luxembourg Centre for Systems Biomedicine of the University of Luxembourg. In addition, he is an Adjunct Professor of Allergology at the University of Southern Denmark and serves as co-coordinator of the study group ‘Signal Transduction’ within the German Society of Immunology (DGfI). His major interests lie in unraveling metabolic and molecular regulatory circuits within the adaptive and the innate immune system. By integrating in vitro with in vivo studies his group aims to gain a comprehensive picture of inflammation and cancer.
Drug resistance in hepatocellular carcinoma (HCC [35, 36]) has been shown to be associated with an altered cellular metabolism. Based on novel multi-component 3D cultures including Kupffer, stellate and endothelial cells, grown in physiologically relevant conditions a metabolic drug screen on drug-resistant and drug-sensitive HCC cells will be integrated with transcriptomic data for target identification.
Prof Iris Behrmann is Professor for Biochemistry and Head of the UL Department of Life Sciences and Medicine. Biologist by training, she did her PhD and post-doctoral research at the German Cancer Research Centre in Heidelberg before becoming group leader at the RWTH Aachen Medical School. In Luxembourg, her team in the Signal Transduction Laboratory works in the field of cancer and inflammation, in particular regarding cellular communication, drug resistance, and the modulatory effects of microenvironmental factors. Prof Behrmann’s research has contributed to the elucidation of the molecular signal transduction mechanisms of interleukin-6-type cytokines via the Jak/STAT pathway.
Preliminary evidence from the consortium suggests that the DNA repair status of GBM cells affects the recruitment of tumour-associated macrophages (TAMs) and the mounting of an innate immune response. Here we will investigate whether DNA repair-based strategies can contribute to turn GBM into an “immunologically hot” tumour. An RNAi screen will be performed in GBM cells to identify the DNA repair factors whose depletion promotes phagocytosis by macrophages.
Dr Eric Van Dyck is a molecular biologist and biochemist who heads the DNA Repair and Chemoresistance research group at LIH’s Department of Cancer Research. His group is developing approaches to better understand the DNA repair and epigenetic mechanisms that operate in adult and paediatric glioblastoma (GBM) and identify critical targets for innovative DNA repair-based therapeutic strategies. Recent achievements include the identification of a DNA repair and cell cycle gene expression signature in adult GBM with perspectives for precision medicine. Current research lines focus on the targeting of tumour propagating cells in GBM as well as on the interrelationship between DNA repair factors and the immune response in cancer.
GBM cells display strong intrinsic plasticity and adapt reversibly to changing microenvironmental stimuli, forming a dynamic ecosystem. The role of tumour plasticity in creating treatment-resistant states is currently less understood. Here we will leverage existing and novel single cell RNA-Seq datasets to investigate transcriptomic changes in treatment-naive and treated tumours. We will apply advanced computational algorithms, including reference-free deconvolution methods, to reveal treatment-resistant states, their molecular signatures and regulators.
Dr Anna Golebiewska is Group leader of the NORLUX Neuro-Oncology laboratory. She has a background in molecular and cellular biology and obtained her PhD in stem cell research. Her work focuses on understanding brain tumour biology, in particular tumour heterogeneity and microenvironment. Her current projects aim to tackle intrinsic plasticity allowing brain tumour cells to adapt and survive external pressures from microenvironment and treatment. Her lab developed a large collection of glioma patient-derived organoids and orthotopic xenografts for preclinical research and drug testing, for which she received the FNR Award for Outstanding Scientific Achievement in 2021.
sEVs represent a complex cell communication system that contributes to immune suppression in cancer through inhibitory immune checkpoint (IC) ligands at their surface. Here we will produce bioengineered sEVs displaying IC receptors acting as scavenger to counteract tumour-derived sEVs within the TME. Engineered sEVs with different combinations of IC receptors will be produced from stromal cells. Functionalities and efficacy of these sEVs will be investigated in advanced preclinical models using CyTOF, imaging flow cytometry and high-resolution microscopy.
Dr Jérôme Paggetti heads the Tumour Stroma Interactions group in LIH’s Department of Cancer Research since 2017. His research in haemato-oncology focuses on the interplay between leukemic cells and their microenvironment in particular the immune system, using patient samples and murine pre-clinical models. The group is composed of 14 members (5 PhD students, 5 postdocs, 1 engineer, 1 scientist and 2 group leaders). He established collaborations with well-known universities and cancer institutes in Europe, published in top journal of the field and received several scientific prizes including the FNR Award for Outstanding Publication in 2016.
The atypical chemokine receptor ACKR3/CXCR7 acts as a key regulator of TME-derived chemokines and controls cancer cell proliferation, survival and metastasis. Our team has recently developed and patented several ACKR3 modulators and identified three compounds blocking its capacity to scavenge chemokines. Here we will establish the anti-cancer activity of these drugs in different in vitro and in vivo models of increasing complexity (organoids/syngeneic/PDXs) available within the consortium, including glioblastoma, breast cancer and leukaemia/lymphoma.
Dr Andy Chevigné studied Biochemistry at the University of Liège (Belgium) and obtained his PhD from the Centre for Protein Engineering (ULiège) and the Laboratory of Applied Genetics (Free University Brussels, ULB). He joined LIH in 2008 to investigate the role of chemokine receptors in HIV-1 entry and became independent group leader in 2011. He is currently Head of the Immuno-Pharmacology and Interactomics group, which has as main research focus the study of chemokine receptors. He is also Deputy Head of Academic affairs at LIH and Lecturer at ULiège. He was co-awarded the Galien prize of Pharmacology 2019. He supervised several postdocs and PhD students with support from funding agencies and private companies.
Projects – WP1 – Novel Cancer Models
Projects – WP2 – Cancer Metabolism
Projects – WP3 – Novel Treatment Strategies
For any question related to CANBIO2, please contact:
We offer 15 fully funded PhD positions with a fixed-term work contract of up to 4 years.
We are seeking excellent and highly motivated candidates holding a Master’s degree in a field related to the topics of the DTU. Very good English language skills are required. The earliest start date will be September 2023.
Please visit our LIH Jobs Portal to apply.