Van Heesch group
Understanding and targeting the dark proteome in childhood cancer.
Proteins are molecular machines that are vital for the functioning of each living cell, but how well do we really know all proteins that are being produced within a tumor? In the Van Heesch group, we investigate the role of a novel class of small proteins called 'microproteins' in childhood cancer. We study microprotein functions and exploit their sometimes high tumor-specificity for immunotherapeutic applications, such as cellular therapies and vaccines. We perform pre-clinical research and combine experimental (sequencing and proteomics) with computational strategies (bioinformatics).
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Sebastiaan van Heesch
Identification and characterization of novel microproteins
Using state-of-the-art genomics and proteomics technologies, we have recently discovered thousands of putative microproteins translated by ribosomes from presumed noncoding RNA in human tissues (van Heesch et al., Cell 2019, Mudge et al., Nature Biotechnology 2022, Sandmann et al., Molecular Cell 2023). As none of these proteins were known to exist, these findings could mean that the human proteome is much more complex than anticipated. They also create a wealth of potential 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 (Hofman et al., Molecular Cell 2024). However, for most microproteins, their precise function and behavior in disease are not known. The Van Heesch group aims to identify and characterize microproteins with important roles in pediatric cancer and devise therapeutic strategies to target them.
Key to the detection of these small proteins is the ribosome profiling (or Ribo-seq) technology, which helps us visualize the (parts of) RNA molecules used in a cancer cell for protein synthesis. In our lab, we apply and integrate state-of-the-art genomics, transcriptomics, translatomics and proteomics technologies, which we combine with targeted knockout and knockin (CRISPR/Cas9), subcellular localization, and interactome analyses to fully understand each microprotein’s mechanism of action.
“To fight cancer, we create personalized catalogs of all mistakes a cancer cell makes while producing protein. We then use these tumor-specific errors against the tumor through targeted (immune) therapies.”
Sebastiaan van Heesch
Research group leader
Exploring the tumor-specific translatome for immunotherapy
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 aims to identify pediatric tumor-specific antigens 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 cell lines or organoids. The aim is to catalog personalized and recurrent putative tumor-specific antigens, detect these with HLA-I immunopeptidomics, and design cellular therapies and vaccines against them.
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