19A. The use of organotypic tissue slices for assessing prevention against treatment-induced side-effects via nutritional preconditioning interventions

Fortunately, most children suffering from cancer survive thanks to effective chemotherapy. However, during treatment and later in life, they are frequently confronted with severe side-effects of their life-saving treatment. This includes numerous features of accelerated aging, seriously affecting quality of life (QoL); rendering this one of the most pressing problems associated with (paediatric) oncology. Here, we aim to investigate whether nutritional preconditioning can effectively prevent chemotherapy-induced toxicities without compromising treatment efficacy. We want to accomplish this by reducing food intake (known as dietary restriction; DR), which triggers in healthy tissues a powerful ‘survival’ response that temporarily suppresses growth and boosts resilience and defence mechanisms, mounting a strong defence against the (genotoxic) damage inflicted by the chemotherapy. Conversely, tumours mostly become more sensitive to chemotherapy, as they are metabolically derailed (overuse glycolysis) and less able to adapt, due to uncontrolled growth.

Urgent questions we want to address are: Can nutritional preconditioning prevent equally well short- and long-term toxicities induced by various chemotherapeutic drugs or inflicted to different tissues? What is the most optimal timing for incorporating nutritional preconditioning into treatment regimens? We will achieve these aims by studying DNA damage, cellular senescence and toxicity parameters in various organoid types, from tumour and healthy tissues, subjected to a diverse panel of chemotherapeutics under normal and nutrient-restricted culture conditions. In parallel, we will assess outcomes in organotypic tissue slices, a novel method recently developed for short-term culturing and testing of small tissue sections from patient biopsies, which in contrast to organoids, maintain tissue architecture. Lastly, the effects of dietary restriction on survival, health status, and (accelerated) aging in tumour-bearing, patient-derived xenograft mice treated with chemotherapy will be measured. If successful, this simple, cheap, safe, globally applicable intervention will have an immediate, major impact on treatment and long-lasting QoL of numerous children with cancer.

Necessary skills for this position:

• Master’s degree in Cancer Biology, Life Sciences, Biomedical Sciences or a related field
• Hands–on experience in cellular and molecular technologies, including cell and/or organoid culture, confocal microscopy, flow cytometry and immunohistology, are preferential
• A background in Cancer or Biomedical Informatics are considered an advantage