Step up the scientific career ladder
During a PhD, a researcher focuses on a topic for several years under the supervision of a senior researcher. Results are published in scientific journals and compiled into a dissertation. After defending this dissertation, the researcher receives the doctoral title, also called PhD, from the university concerned. In this case, Utrecht University. Since the opening of the Máxima five years ago, over 60 PhD students have received their doctorate.
As of today, Michael Meister will proudly be a doctor in research. He explains: ‘I knew early on that I wanted to become a pediatric oncologist. The positivity of children really appeals to me. As well as the fact that as a doctor you can help across a broad spectrum and build an often long-term relationship with the child and parents. As a future pediatric oncologist, I want to help children as best I can. For me personally that also includes scientific research as an integral part of my work. I am therefore very happy and proud to receive my PhD title today.’
Targeting cell signaling pathways gone awry
Rhabdomyosarcoma is a soft tissue tumor diagnosed in 25 children in the Netherlands each year. Despite a tough course of treatment with chemotherapy, radiotherapy and often surgery, more than half of children with high-risk rhabdomyosarcoma do not survive their disease. So, research into better, targeted therapies is desperately needed to improve survival rates and the quality of life for these children. To do this, it is important to better understand the biology and development of the disease. In his doctoral research, Meister studied, among other things, so called cell activating signaling pathways.
Meister says: ‘It is known that tumor cells are very good at bypassing conventional therapies, so the dysfunctional cells are not cleared and can continue to grow. This is caused by the disruption of the normal signal transduction in the cells. In the case of rhabdomyosarcoma, we saw that the so-called Hedgehog signaling plays an important role in the circumvention of cell death. Therapeutics that specifically target this, also called Hedgehog Pathway Inhibitors, may therefore be a promising therapy option and lead for further research.’
3D mini-tumors
This research on signaling pathways gone awry used so-called cell lines. However, tumor organoids, 3D mini-tumors grown in the lab, reflect tumor characteristics in patients more closely: Meister and fellow researchers from the former Holstege group and the Drost group therefore collected tumor tissue from 46 children who had been treated for rhabdomyosarcoma in the Máxima Center. They tested different methods of growing the mini-tumors. In 41 percent of the samples, 19 in total, model. The research was published and highlighted on the cover of the journal EMBO Molecular Medicine.
Michael Meister: ‘With these organoids, we are making an important addition to the arsenal of preclinical models of rhabdomyosarcoma. This will allow us to greatly accelerate our research into this rare form of childhood cancer and address entirely new research questions. In the future, we can use the organoids to help finding the optimal therapy for each child with rhabdomyosarcoma.’
Understanding the tumor-microenvironment of rhabdomyosarcoma
Meister was intrigued by indications of retained tumor cell heterogeneity in the developed rhabdomyosarcoma organoids. Hence he, and his colleagues Jeff DeMartino, PhD student in the Drost group, and Lindy Visser, postdoc working in the Máxima Center’s single cell genomics facility, studied the cellular composition of these tumors using so-called single cell RNA-sequencing. Meister: ‘This study gave us an unprecedented insight into the cellular composition of rhabdomyosarcoma tumors, both concerning heterogeneity between tumor cells but also concerning normal cells in the tumor like immune cells. The latter are thought to play a pivotal role in new immunotherapeutic approaches.’ This study was recently published in Nature Communications.
Getting further together
Scientific research and challenges are inseparable. However, Meister took up these with enthusiasm: 'It is inspiring that so many driven specialists work at the Máxima. Research is a collaborative sport and the studies described in my thesis were only possible due to the immense contributions of my colleagues, both practically and intellectually. I am deeply grateful that together with these fantastic people, I could work on projects that hopefully will improve prognosis for children with rhabdomyosarcoma.’
Michael Meister's research was funded by core funding from KiKa to the Princess Máxima Center, with further support from the Deutsche Forschungsgemeinschaft (DFG).