Multi-System Cancer Biology – Prof. Holger Auner (CHUV)

Multisystem cancer biology: targeting the interplay between intra- and extracellular proteostasis

Prof. Holger Auner

All human cells must assemble – and later break down – the right proteins at the right time and in the right quantities. To do this, they need to use and recycle building blocks such as amino acids, and provide energy for the molecular machines that make and break down proteins. The fine-tuned orchestration of these processes represents a considerable challenge that cells must continually master, as a correct cellular “proteome” (the entire set of proteins) is essential for the proper functioning of cells and for the health of the tissues and organs in which they reside.  As a result, a myriad of diseases often linked to age are linked to the inability of cells to keep the proteome in order.

Cancer cells usually grow and multiply faster than normal cells. They are therefore thought to be particularly dependent on the processes that regulate the proteome in order to keep up with high protein turnover. Disrupting these mechanisms is a promising therapeutic approach and has already led to new treatments for some cancers, such as multiple myeloma, a malignant disease of the bone marrow. Our team is working to better understand how different cancers try to keep their proteome in order, and to find ways to target these mechanisms with new drugs. One of the molecules we are interested in is called GCN2. It regulates how cells respond when their amino acid stores run low. We want to understand how to safely turn off GCN2 in cancer cells so that their proteome fails, killing them, while healthy tissue is largely spared. We know that this approach works well experimentally in some cancer cells, but not in others. One goal of our research is to identify the features that make cancer cells dependent on GCN2, which would help identify cancer patients (prior to therapy) that are likely to respond to treatments with drugs that target GCN2. To do this, we use a so-called systems biology or multi-omics approach, in which different technologies are used to study several cellular processes in parallel (e.g., to understand how cellular metabolism changes when certain genes are actively transcribed and translated into proteins). We and many others believe that such a holistic approach to molecular cancer research has great potential to identify previously unknown cancer cell vulnerabilities. To find and target these Achilles’ heels, we collaborate with academic colleagues and research partners from the biotechnology and pharmaceutical industry.