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 a prime example of a cancer that is highly 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 MSCA-DN funded 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. 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. Here, the 3 positions at the Amsterdam UMC (of a total of 10) are offered. Each position offers a unique set of opportunities and challenges as explained below.

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.

Each position has its own signature, aims, and requirements. All three start Februart 2024 and are for 4 years.
Please find the positions below and indicate in your application which position you are applying for:

Position 1: The dynamics of resistance and cellular plasticity.
HOST: Amsterdam UMC, location AMC
SUPERVISORS: dr. Maarten Bijlsma (m.f.bijlsma@amsterdamumc.nl) and prof. Hanneke van Laarhoven
DESCRIPTION: Esophageal adenocarcinoma (EAC) cells quickly develop resistance to therapy. 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 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).

Position 2: Multi-parametric imaging for studying therapy resistance in esophageal cancer
HOST: Amsterdam UMC, location AMC
SUPERVISORS: prof. Gustav Strijkers (g.j.strijkers@amsterdamumc.nl) and dr. Bram Coolen (b.f.coolen@amsterdamumc.nl)
DESCRIPTION: This project aims to tackle therapy resistance in 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).

Position 3: 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)
DESCRIPTION: One of the problems contributing to the poor prognosis of EAC is resistance to neoadjuvant chemoradiotherapy (nCRT) which is observed in ~30% of patients. We have 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 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 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 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.

The three PhD positions are very different but all need talented and ambitious individuals eager to perform top-notch science in a large multidisciplinary and international team.

Position 1:

• 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.

Position 2:

• 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.

Position 3:

• A master’s degree in life sciences, other (bio)medical sciences or related.
• Basic bioinformatic and cell culturing skills.

• Plenty of room for your drive to shape the care of tomorrow.
• Working on large-scale and your own research, with motivated colleagues from all corners of the world.
• A contract for 12 months with the intention of an extension.
• Salary scale OIO: € 2,901 to € 3,677 gross with full-time employment
• Besides a good basic salary, you will receive 8.3% end-of-year bonus and 8% vacation allowance.
• Pension accrual with BeFrank, a modern, comprehensible and fairly priced pension.
• Excellent accessibility by public transport and reimbursement of a large part of your travel expenses. We also have a good bicycle plan.

Amsterdam UMC

The Amsterdam UMC is nationally leading in the care for, and research on, esophageal cancer. The departments in which the positions are offered are all internationally recognized teams that aim to perform high-impact science.

The positions offered are part of a larger European PRESSURE consortium (pressurenetwork.eu), coordinated by the Amsterdam UMC. Through meetings, secondments and collaborations, the PhD candidates will have access to a unique range of expertises and research tools.