Marcel Kool/Jens Bunt
1A. R-loops in pediatric brain tumors: from cause to cure?
Pediatric brain tumors remain a big challenge and they have a large contribution to the mortality rate of pediatric cancers. To develop better and more specific treatment strategies, this project will investigate the biological roles of R-loops, unique three-stranded DNA:RNA hybrids. We previously discovered that R-loops play an important role in embryonal tumors with multi-layered rosettes (ETMR). We aim to better define the role of R-loops to brain tumorigenesis and biology of pediatric brain tumors in general, as well as to determine whether R-loops could be a biomarker for specific targeted therapies.
R-loops pose a threat to DNA integrity and therefore can lead to mutations. To uncover whether R-loops contribute to the formation of oncogenic mutations in brain progenitor cells, human brain organoid models will be used. Immunostainings and genomic techniques will determine whether R-loop levels correspond with DNA damage and genomic aberrations at the sites of tumor-specific oncodrivers.
Oncogenic transformation itself may also affect R-loop formation, because oncodrivers can increase transcription and replication, or directly act on R-loops. The relationship between different oncodrivers and R-loops will be investigated on a cellular and molecular level. R-loop-specific DNA:RNA immunoprecipitation in patient-derived and genetically engineered tumor models will elucidate whether R-loops presence correlates with oncogene activity and genomic instability.
Tumors with high R-loop levels, such as ETMR, appear more sensitive to drugs inducing DNA damage or inhibiting subsequent repair, because R-loop abundance leaves DNA more vulnerable to damage. The overall abundance of R-loops will be assessed in different brain tumors by immunostaining. To evaluate R-loops as a potential biomarker for therapy, this data will be correlated with tumor and oncodriver characteristics and drug sensitivity data.
This project will provide fundamental insides in the role of R-loops in brain tumor development and biology and inform further preclinical drug testing, using R-loops as biomarkers.
Necessary skills for this position:
- Master of Science degree in (molecular) biology, biomedical sciences, neurosciences, or related disciplines
- Proven laboratory experience, preferable with molecular and genomics techniques, cell culture, immunohistochemistry and/or imaging
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