Marc Remke1,2,3, Guido Reifenberger2 and Arndt Borkhardt3
1Division of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) - partner site Essen/Düsseldorf, Düsseldorf, Germany
2Institute of Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
3Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Proteogenomics and high-throughput drug screening for novel brain tumor therapies – it takes two to tango
Introduction: Proteogenomics provides an integrative, multi-omics perspective on pediatric brain tumor biology. Here, we describe the analytical pipeline and demonstrate the added value of this approach to improve biological classification, and, to reveal novel therapeutic vulnarabilities for medulloblastomas, the most common malignant brain tumor in childhood.
Materials and Methods: Our proteogenomics approach utilizes matched next-generation sequencing data (RNAseq, miRNAseq, WGS), high-resolution DNA methylation / copy number profiling data, and (phospho-) proteomic profiling data to determine the biological heterogeneity of medulloblastomas using similarity network fusion. Integrative genomics dissects aberrant pathway activation in biological subgroups. Lastly, in-house high-throughput drug screening data using conventional and phase III/IV clinical trial drugs in medulloblastoma culture models complements our proteogenomics approach.
Results: Using proteogenomics in primary human medulloblastoma, we unraveled distinct epigenetic and post-translational regulation leading to highly divergent oncogenic signaling and kinase activity profiles in medulloblastoma subgroups. Specifically, transcriptomic and (phospho-)proteomic analyses reveal novel miRNA/long non-coding RNAs or aberrant pathway activation as oncogenic drivers in medulloblastoma subgroups, respectively, which were not previously apparent in single layer omics studies.
Conclusion: Overall, our integrative proteogenomic approach identifies previously unknown oncogenic pathway activation and potential therapeutic vulnerabilities in the most common malignant brain tumor in childhood.
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