Van Heesch group

PI: Sebastiaan van Heesch

“We’re diving into an unexplored world of novel small proteins whose existence until recently was completely unknown. It’s the 'dark matter' of the cancer proteome.”

Sebastiaan van Heesch - PI

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. The aim of the Van Heesch group is to identify and characterize microproteins with important roles in pediatric cancer and devise therapeutic strategies to target them.

Figure: three examples of newly discovered microproteins produced from long noncoding RNAs, and their predicted alpha-helical 3D structures.
Localizing to the mitochondria, these microproteins can influence vital cellular processes such as energy metabolism. Source: van Heesch et al., Cell 2019

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. Interestingly, some of the lncRNA genes that produce microproteins have previously been implicated in cancer. Still, it remains unclear whether the RNA or the microprotein is responsible for the cancer-related functionality. To answer these and other open questions, 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 catalogues of all mistakes a cancer cell makes while producing protein. We then use these tumor-specific errors against the tumor through targeted (immune) therapies.”

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 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.