Proteins in cells are subject to various chemical modifications that regulate their activity. One common modification consists in the attachment of ubiquitin molecules through a cascade of enzymes. Genetic defects in this ubiquitin cascade are the cause of many acquired and hereditary diseases, including neurodegenerative, immune and tumour disorders. Due to the complex biology and transient nature of ubiquitin modifications, research in this field still lacks a valid approach capable of providing answers to its function in disease.
To fill this knowledge gap, a project by Prof. Jean-Philippe Theurillat of the Institute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana, Faculty of Biomedical Sciences) recently received a prestigious Sinergia Grant of 2,5 million CHF from the Swiss National Science Foundation (SNSF). The multidisciplinary project will be conducted under the direction of the IOR and with the participation of other research groups of excellence including the Proteomics platform of the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University in the United States, the Institute of Surgical Pathology at the University Zurich, and Institute of Pharmaceutical Biochemistry at the University of Geneva.
The overall objective of the project is to develop and optimise methods and drug-like chemical substances to detect and influence changes within the ubiquitin cascade in the context of cancer. The developed approaches and expected results will help to understand how ubiquitin changes of distinct proteins enable tumor growth and how this knowledge can be exploited to design more specific therapeutic interventions in cancer patients whose tumors are driven by alterations in the ubiquitin cascade.
To reach their challenging goals, the research groups under the lead of Prof. Theurillat will use a multidisciplinary approach using biochemical methods to detect ubiquitin modifications in clinical tumor specimens and patient-derived cell culture models along with techniques to visualize the interaction of specific proteins and small chemical molecules. According to Prof. Theurillat: “The research project will establish an innovative and effective framework to understand and address the molecular mechanisms related to ubiquitin dysregulation in cancer, also applicable in the context of many other diseases”.