Genomics, RNA and systems biology

Sebastiaan van Heesch

Our Research

The van Heesch group
Our lab has recently been established at the Princess Máxima Center for Pediatric Oncology. We have a strong interest in systems biology applications to help advance pediatric cancer patient care. Our lab consists of both a wet- and dry lab, with multiple lab members with complementary expertises working together on challenging projects. We combine a strong interest in fundamental molecular biology (mainly RNA biology and gene expression control) with the development of applications that we hope will directly benefit patients, such as novel therapies for difficult to treat pediatric cancers. The paragraphs below give a brief overview of our research goals. If you have any questions feel free to reach out! For more information on our work and publication record please see: https://scholar.google.com/citations?user=B6nKmnwAAAAJ&hl=nl

Identification and characterization of novel microproteins in pediatric cancer
Using state-of-the-art genomics and proteomics technologies, we have recently discovered thousands of microproteins translated by ribosomes from presumed long noncoding RNAs (lncRNAs) in human tissues (van Heesch et al., Genome Biol 2014, van Heesch et al., Cell 2019, Gaertner & van Heesch et al., eLife 2020). As none of these proteins were known to exist, this vastly expanded the human proteome and created a wealth of novel protein functions to investigate.
Because of their small size, microproteins can be potent influencers of all kinds of cellular processes and pathways – including those important for cancer. However, for most microproteins their precise function and behavior in disease are not known. One of the aims of the Van Heesch group is to identify and characterize microproteins with important roles in pediatric cancer and devise therapeutic strategies to target them.
To find these microproteins, we use the Ribo-seq technology, with which we capture actively translating ribosomes and the RNA templates they translate into protein. This on the one hand gives a quantitative measure of gene expression at the level of translation, e.g. how many ribosomes are translation how much RNA template, and with what efficiency? To what extent is translational control crucial in determining final protein levels in a cell? Integrating genomic variation (structural and single nucleotide), RNA expression data (incl. de novo assembled transcriptomes), Ribo-seq and mass spectrometry-based proteomics, we can evaluate the contribution of each layer of gene expression to protein production and define the impact of (disease-causing) genetic variability on the gene expression landscape.

Exploring the tumor-specific translatome for immunotherapy
Using a similar multi-OMICs range of high throughput technologies another aim of our lab is to identify tumor-specific targets for novel immunotherapeutical applications for pediatric cancer. Immunotherapy has revolutionized the treatment of cancer in adults, but its application to childhood cancer is still very limited. As part of the Princess Máxima Center’s broader strategy to develop immune therapy options for pediatric cancer patients, the Van Heesch group will focus on the identification of pediatric tumor-specific epitopes that can subsequently be targeted with immunotherapy.
To find the best targets, we use a combined genome (DNA), transcriptome (RNA) and translatome (protein production) monitoring strategy for solid tumor tissue and patient-derived organoids. Even in the absence of extensive genetic variation, this approach can yield epitopes specific to the tumor that arise through aberrant RNA translation activity by ribosomes. The aim is to catalogue these differences in translation in personalized, patient-specific databases, from which we select the most promising, tumor-specific peptides for targeting.

Research Group

Sebastiaan van Heesch
Group name: van Heesch group
Research field: Genomics, RNA and systems biology
Genomics, Genome Biology, Data Integration
Department: Princess Máxima Center for Pediatric Oncology

Contact

Heidelberglaan 25
3584 CS
Utrecht
Building: Princess Máxima Center for Pediatric Oncology
s.vanheesch@prinsesmaximacentrum.nl
https://research.prinsesmaximacentrum.nl/en/research-groups/van-heesch-group