In 2035, cancer will have become the leading cause of death in the EU. Therapy resistance is a key contributor to high recurrence rates, morbidity, and mortality. Esophageal adenocarcinoma (EAC) is the most common type of esophageal cancer in the Western world, and aprime example of a cancer that ishighly resistant to therapy. Despite recent developments of treatment strategies, long-term survival remains low. Prominent factors that contribute to the poor outcome of EAC are a high degree of acquired resistance, and heterogeneous responses to therapies. Additionally, to improve EAC treatment outcome, molecular and cellular mechanisms of resistance need to be further understood.
The PRESSURE consortium brings together expert groups from the Netherlands, Germany, Italy, Sweden, Czech Republic, France, and Denmark, to address key challenges that preclude the effective treatment of EAC: A consensus treatment in the EU based on real-world efficacy data is lacking. Establishing such data and unified treatment will avoid the detrimental effects of some therapies. Likewise, the current fragmentation of expertise and tools across Europe prevents an effective development of new approaches. PRESSURE members have independently amassed a wealth of samples, disease models, clinical data, scientific know-how, and cutting-edge technologies. In the consortium, these elements will be joined to develop novel and optimized treatment strategies and diagnostics. We will employ 10 researchers to address these scientific challenges by performing research in academic and industrial groups, and by doing so receive exhaustivetrainingacross relevant disciplines and sectors.
POSITIONS OFFERED
Nine PhD position are currently offered, of which one will start November 2023 (DC7), and eight on February 2024. A tenth position (DC10) starting on November 2024 will be posted at a later moment. The offered individual research projects are biomedical, epidemiological, and biophysical in nature. Below are listed descriptions of the available positions, also stating candidate requirements, and planned secondments to other consortium members.
Note that the MSCA-ITN mobility clause applies; the applicant may not have spent 12 months or more in the past 3 years in the country where the position is offered. Candidates may not already hold a doctoral degree. Candidate must be eligible to work according to your host country’s regulations (for instance visa requirements), and to work in other European countries for secondments and meetings.
WORK LOCATIONS AND INDIVIDUAL RESEARCH PROJECTS
DC1: The dynamics of resistance and cellular plasticity.
HOST: Academic Medical Center, Amsterdam, the Netherlands
SUPERVISORS: dr. Maarten Bijlsma (m.f.bijlsma@amsterdamumc.nl) and prof. Hanneke van Laarhoven
DURATION: 48 months, starting February 2024
PROFILE: A candidate with a Master's degree in life sciences, other (bio)medical sciences, or related. Proficiency in basic bioinformatics, R, animal experiments and cell culturing skills are a plus.
DESCRIPTION: Esophageal adenocarcinoma (EAC) cells quickly develop resistance to therapy, necessitating a deeper understanding of these mechanisms. This research project focuses on quantifying the clonal dynamics associated with therapy resistance. Using patient-derived models from the PRESSURE platform, the researcher will establish lineage-tracing models via lentiviral transduction, incorporating inducible and constitutive multicolor systems. The study will analyze clonal dynamics in untreated and treated EAC in vivo models to distinguish whether resistance in treated preclinical EAC models arises from population-wide adaptation or selective pressure favoring resistant clones. Additionally, the researcher will integrate omics data (RNA, proteomics, spatial profiling) with lineage tracing, linking the newly discovered mesenchymal EAC subtype to clonal dynamics and resistance mechanisms. The research will explore epigenetic landscapes linked to subtype differentiation and clonal expansion patterns. The ultimate goal is to uncover innovative therapies that bypass resistance mechanisms and optimize existing treatments. The AMC provides all necessary models and tools, with dedicated technical support for the researcher. This research, within a concise framework, addresses the urgent need to combat therapy resistance in EAC. As part of the project, the doctoral candidate will intern at the Karolinska Institute (Sweden, 3 months, supervisor Fredrik Klevebro) and University of Palermo (Italy, 2 months, supervisor Simone di Franco).
DC2: Multi-parametric imaging for studying therapy resistance in esophageal cancer
HOST: Academic Medical Center, Amsterdam, the Netherlands
SUPERVISORS: prof. Gustav Strijkers (g.j.strijkers@amsterdamumc.nl) and dr. Bram Coolen (b.f.coolen@amsterdamumc.nl)
DURATION: 48 months, starting February 2024
PROFILE: Seeking a candidate with a Master's in Technical Medicine, (Bio)medical Sciences, or a related field. Must have a strong interest in imaging technology and animal-based research.
DESCRIPTION: This project aims to tackle therapy resistance in esophageal adenocarcinoma (EAC) by advancing state-of-the-art, non-invasive imaging methods for real-time analysis of the tumor microenvironment (TME). The selected candidate will conceptualize and create an innovative high-resolution multiparametric imaging system to detect molecular shifts within the TME, offering insights into treatment responsiveness. The imaging toolbox includes MRI, with a range of contrast methods such as T1-, T2-, T2*- and diffusion-weighted imaging. Data collection will involve both xenograft mouse models and human subjects. Additionally, ultrasound and photoacoustic techniques will be used to assess vascular and oxygenation status of the tumor. Machine learning algorithms will help integrate these various data streams into meaningful TME insights. The AMC furnishes all necessary tools and offers specialized technical support, creating a conducive setting for tackling EAC therapy resistance. The position includes 3-month internships at the Karolinska Institute (Sweden, supervisor Magnus Nilsson) and the University of Leipzig (Germany, supervisor Florian Lordick).
DC3: The role of the tumor immune microenvironment in primary chemo(radio)therapy resistance: identifying immune targets to improve outcome.
HOST: VU University Medical Center, Amsterdam, the Netherlands
SUPERVISOR: dr. Sarah Derks (s.derks@amsterdamumc.nl)
DURATION: 48 months, starting February 2024
PROFILE: master’s degree in life sciences, other (bio)medical sciences or related. Basic bioinformatic and cell culturing skills.
DESCRIPTION: One of the problems contributing to the poor prognosis of esophageal adenocarcinoma (EAC) is resistance to neoadjuvant chemoradiotherapy (nCRT) which is observed in ~30% of patients. in a previous study, we found that lack of response to nCRT is strongly associated with T-cell suppression. To improve response to nCRT we need to identify and target the mechanisms EACs use to limit T cell infiltration and suppress T cell function. To this end, the researcher will explore existing RNA-Seq data and spatial transcriptomics (GeoMx) data to identify immune cell features associated with resistance to nCRT and systemic therapies. Next, candidate resistance-associated immunological factors will be functionally tested in the EAC model panel, focusing on 3D ex vivo cultures of EAC cell lines or patient-derived organoids (VUmc) and immune cells. 3D co-cultures models will ultimately be used to test novel treatment strategies. The development of tumor-immune co-culture systems will provide an opportunity for the researcher to work with tumor and immune cells and understand their interplay. The researcher will be embedded in the team of Sarah Derks at Amsterdam UMC, and will intern at React4life (Italy, 3 months, supervisor Silvia Scaglione), to test organ on chip platforms and at the AMC (Netherlands, 3 months supervisor Maarten Bijlsma) for additional bioinformatics training.
DC4: Functional analysis and validation of candidate targets, relevant in adaptive tumor response: from acquired resistance to acquired vulnerability and treatment optimization
HOST: University of Leipzig, Medical Faculty, Leipzig, Germany
SUPERVISORS: Prof. Dr. Achim Aigner (achim.aigner@medizin.uni-leipzig.de), Prof. Dr. Florian Lordick (florian.lordick@medizin.uni-leipzig.de), Prof. Dr. Ines Gockel (ines.gockel@medizin.uni-leipzig.de)
DURATION: 36 months, starting February 2024
PROFILE: Master’s degree in life sciences, pharmacy, other (bio)medical sciences or related. Skills and practical experience in cell biology, molecular biology, and standard cell culture; basic skills in bioinformatics.
DESCRIPTION: Chemotherapy for gastric cancer is increasingly combined with targeted therapeutics such as HER2-directed agents. However, acquired resistance is a critical issue. To define better therapeutic options, we aim to characterize molecular alterations associated with treatment resistance. From these alterations, we will derive secondary therapeutic targets according to the concept of acquired vulnerability. Within this project, we will use complex in vitro and ex vivo models, including spheroid cultures based on standard cell lines as well as mixed spheroid cultures (i.e., tumor cell spheroids including fibroblasts, endothelial cells, others). In addition, we make use of tissue slice cultures derived from tumor xenografts. Using these models, candidate therapeutic agents will be tested. Moreover, RNAi-mediated knockdown strategies will be used to verify candidate targets crucial for cancer cell survival. On this basis, we’ll aim to define novel combination therapies overcoming treatment resistance. The advanced tumor models are well-established in Leipzig. The applicant will be part of an experienced team of colleagues and supervisors that will provide active support. Secondments are planned to the AMC (Netherlands, supervisor Maarten Bijlsma, 2 months) and Nordic Biosciences (Denmark, supervisor Nicholas Willumsen, 2 months).
DC5: Identification of in situ immune and metabolic signature associated with resistance to therapy in esophageal adenocarcinoma
HOST: Montpellier Cancer Research Institute
SUPERVISOR: Dr. Nathalie BONNEFOY (nathalie.bonnefoy@inserm.fr)
DURATION: 36 months, starting February 2024
PROFILE: master’s degree in life sciences, biomedical sciences or related. Basic bioinformatics and oncoimmunology skills.
DESCRIPTION: Esophagogastric adenocarcinomas, including localized cases, often resist treatments, with a high likelihood of progression or relapse after initial therapy. This resistance may result from immune checkpoint expression (e.g., PD-1/PD-L1, LAG-3, CD39/CD73) inhibiting treatment's immune-modulating effects and the intratumoral microenvironment's (HiMET) high heterogeneity. HiMET encompasses cellular, genetic, transcriptional, and metabolic diversity. Cancer cells adapt their metabolism to support abnormal growth and survival based on their location. Recent research indicates that this metabolic HiMET influences the interplay between tumor evolution and immune infiltration. Imaging mass cytometry (IMC) is an innovative imaging technique enabling the study of over 40 markers at the single-cell level. Dr. Bonnefoy's team (Immunity and Cancer), in collaboration with Dr. Le Cam's team (Molecular Oncogenesis), has developed antibody panels for investigating the immune and metabolic aspects of the tumor microenvironment. This dissertation project aims to characterize the immuno-metabolic signature of esophageal cancer's tumor microenvironment using IMC and spatial transcriptomics. The goal is to identify predictive biomarkers for oxaliplatin response and potential new therapeutic targets. Research visits to the AMC (Netherlands, supervisor Maarten Bijlsma, 3 months) and VUmc (Netherlands, supervisor Sarah Derks, 3 months) are planned.
DC6: Outcomes of multimodality treatment of esophageal adenocarcinoma based on a population-based cohort study and immunologically defined cancer subtypes
HOST: Karolinska Institutet, Stockholm, Sweden
SUPERVISORS: Prof. Magnus Nilsson, Dr. Fredrik Klevebro (fredrik.klevebro@ki.se), Dr. Andrea Ponzetta
DURATION: 48 months, starting February 2024
PROFILE: master’s degree in life sciences, or other (bio)medical sciences. Basic biostatistics skills and knowledge in tumor biology/immunology.
DESCRIPTION: The aim of this project is to increase knowledge about the outcomes of treatment of esophageal adenocarcinoma (EAC), including survival, resection rate, complications, and recurrent disease. The project includes epidemiologic studies in large European population-based prospective cohorts of patients with EAC. The student will work with prospective standardized biobank sample collection. The project will also aim to identify immunologically defined subtypes of EAC with impact on treatment outcomes, including treatment response and survival. The project will provide novel insights into immune-related anti-tumor mechanisms and their association with treatment response and survival based on tumor characteristics and patient classification based on tumor-infiltrating immunological signatures. This has the potential to identify immunological subtypes and evaluate their impact on treatment outcomes, including treatment response and survival. The researcher will perform secondments to the IKNL (Netherlands, supervisor Rob Verhoeven, 3 months) and VUmc (Netherlands, supervisor Sarah Derks, 3 months).
DC7: Identification and validation of esophageal adenocarcinoma cancer stem cell biomarkers associated with a hybrid epithelial/mesenchymal (E/M) resistant phenotype.
HOST: University of Palermo, Palermo, Italy
SUPERVISOR: Prof. Giorgio Stassi (giorgio.stassi@unipa.it), Dr. Simone Di Franco (simone.difranco@unipa.it)
DURATION: 36 months, starting November 2023
PROFILE: master’s degree in life sciences, other (bio)medical sciences or related. Basic bioinformatics, cell culturing and molecular biology skills.
Note that this position is also offered here: https://euraxess.ec.europa.eu/jobs/149676
DESCRIPTION: Esophageal adenocarcinoma (EAC) is notorious for its resistance to existing therapies, necessitating the development of improved treatment approaches. This project's primary objective is to discover and validate cancer stem cell biomarkers linked to a hybrid epithelial/mesenchymal (E/M) phenotype. This E/M phenotype provides vital support to cancer cells throughout various stages of tumor progression, where maintaining both epithelial and mesenchymal characteristics is crucial for survival under microenvironmental pressures and drug exposure. The goal is to identify prognostic biomarkers associated with the E/M phenotype. This research project employs a comprehensive approach, utilizing in vitro assays (proliferation, clonogenic, soft agar, invasion, and migration assays) and in vivo models (subcutaneous, orthotopic, and intrasplenic injection) based on tumor organoids to deepen our understanding of therapy resistance in both EAC and gastric cancer. Spatial transcriptomic analysis will be employed to assess tumor-stroma crosstalk by examining the expression and localization of specific cancer cell biomarkers. These identified biomarkers will undergo rigorous validation in both in vitro and in vivo settings. The findings from these preclinical studies hold the potential to pave the way for innovative anti-tumor therapies for the benefit of EAC patients. Research visits are planned to the AMC (Netherlands, supervisor Maarten Bijlsma, 4 months) and Nordic Biosciences (Denmark, supervisor Nicholas Willumsen, 3 months).
DC8: Advanced proteomic approaches to develop novel therapeutic approaches for esophageal carcinoma
HOST: Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czechia
SUPERVISOR: Dr. Radka Lordick Obermannová, Ph.D. (obermannova@mou.cz)
DURATION: 36 months
PROFILE: master’s degree in life sciences, biomedical sciences or related. Basic molecular/cell biology, and proteomics skills.
DESCRIPTION: Esophageal carcinoma is a global health challenge marked by high morbidity and mortality rates. Despite treatment advancements, therapy resistance remains a significant hurdle, driven by intricate signaling pathways governing tumor growth, metastasis, and treatment responses. The offered research project focuses on these pathways using cutting-edge proteomic techniques. Our primary objective is to pinpoint pivotal signaling pathways in esophageal cancer's progression and therapy resistance. Advanced phosphoproteomics analysis will systematically profile and map phosphorylation events within these pathways, shedding light on abnormal activation and potential therapeutic targets. We will experimentally evaluate inhibitors and antibodies targeting these pathways, uncovering their impact on tumor growth, metastasis, and therapy resistance. This comprehensive understanding may also identify potential therapy response biomarkers. In summary, our research addresses esophageal carcinoma's therapy resistance through a deep dive into signaling networks, offering potential breakthroughs for more effective treatments in a concise and focused manner.
DC9: The role of altered extracellular matrix turnover and its impact on esophageal cancer
HOST: Nordic Bioscience A/S, Herlev, Denmark
SUPERVISORS: dr. Nicholas Willumsen (nwi@nordicbio.com), dr. Neel Ingemann Nissen (nin@nordicbio.com)
DURATION: 36 months, starting February 2024
PROFILE: Candidate holds an MSc degree in biology, biomedicine, or related fields, with strong English communication skills. They excel in organizing lab work and troubleshooting, with a preference for prior experience in cell culture, ELISA development, or statistical analysis of clinical data.
DESCRIPTION: The collective of non-tumor cells called stroma is increasingly recognized as an important contributor to disease progression and therapy response. Furthermore, the stroma is continuously remodeled and the dynamics of this bear relevance for treatment responses. Given the abundance of stromal cells and material in tumors, molecules that originate in this compartment can be readily detected in the blood of patients, and be utilized as biomarkers. Patient stratification for or against certain treatments is important to improve treatment outcome, however biomarkers to effectively do so, are currently lacking. Nordic Biosciences protein fingerprint technology platform will be leveraged to address and develop and validate non-invasive biomarker panels for stroma dynamics to predict therapy response. This is expected to yield biomarkers for current treatments but also identify novel targets and agents that allow perturbation of the stroma specifically. Candidate genes or gene signatures will be validated in biobanked patient material (tissue, blood), with a focus on secreted proteins to yield non-invasive predictive biomarkers. Existing stromal biomarker targets of current interest will be tested in novel material and models. Research visits are planned to UNIPA (Italy, supervisor Giorgio Stassi, 2 months) and AMC (Netherlands, supervisor Hanneke van Laarhoven, 1 month).
DC10: Position will open in 2024.
HOST: React4Life, Genoa, Italy
SUPERVISORS: dr. Silvia Scaglioni (s.scaglione@react4life.com),
DURATION: 36 months, starting November 2024
Requirements
- Research Field
- Biological sciences » Biology
- Education Level
- Master Degree or equivalent
- Research Field
- Medical sciences » Cancer research
- Education Level
- Master Degree or equivalent
Skills/Qualifications
Please refer to the individual positions offered.
Specific Requirements
Please refer to the individual positions offered.
- Languages
- ENGLISH
- Level
- Good
- Research Field
- Biological sciences » BiologyMedical sciences » Cancer research
- Years of Research Experience
- None
Additional Information
Benefits
Selected candidates will receive an attractive salary in accordance with the MSCA regulations for Doctoral Researchers. The exact (net) salary will be confirmed upon appointment and is dependent on local tax regulations and on the country correction factor (to allow for the difference in cost of living in different EU Member States). The salary includes a living, mobility, and family allowance (if applicable). The guaranteed PhD funding for 36 months (i.e., EC funding, additional funding is possible, depending on the local Supervisor, and in accordance with the regular PhD time in the country of origin).
Eligibility criteria
Note that the MSCA-DN mobility clause applies; the applicant may not have spent 12 months or more in the past 3 years in the country where the position is offered. Candidates may not already hold a doctoral degree. Candidate must be eligible to work according to your host country’s regulations (for instance visa requirements), and to work in other European countries for secondments and meetings.
Selection process
Deadline for application is 1/11/2023. Note that your application may be forwarded to other Beneficiaries in the consortium.
Please include the following documents:
- Letter of motivation/research statement (2-3 pages). This should include a description of past work, but also a vision on how you see yourself fit in the consortium and the position you are applying for.
- Curriculum vitae (CV)
- Contact information for 2-3 reference