Role of C16orf72 in Response to Complex and Multifactorial Cancer-Associated Molecular Stresses

A major strategy in anti-cancer efforts is to define the oncogenes that are aberrantly activated in cancers and develop drugs that block their function. Unfortunately, cancer cells often develop resistance to these targeted therapies. Besides oncogenes, cancer cells are often dependent on nonessential cellular factors that become essential in the context of the cancer and drug treatment. Our work thus far has focused on a basic biological question that has broad relevance across cancer biology: why are cancer cells resistant to the harsh stresses that characterize cancer cell growth, the tumor environment, and cytotoxic therapies? Indeed, cancer cells are known to adapt and survive harsh stress conditions which kill normal cells. These stresses include errors in normal processes, like the building of proteins, that are greatly increased to meet the aggressive growth that characterizes cancer cells. They also include additional challenges, such as those brought on by cytotoxic chemotherapies. These stresses nearly always occur in complex combinations. For example, cancer cells in the core of a solid tumor, have a lower access to oxygen – but they also become nutrient-starved, acid-exposed (because of their unusual metabolism), and inflamed. Identifying factors(s) that help cells tolerate diverse stresses may uncover novel strategies to treat common cancers while suppressing anti-cancer drug resistance. What powers cancer cell stress resilience? We exposed cancer cells to many stresses and assessed which factors were activated. Next, we developed an algorithm to predict factors important for multi-stress resilience. This revealed a previously unknown factor – the protein known as C16orf72. We confirmed that when cells lose C16orf72, they are less tolerant to many types of stress. C16orf72 seems to help cells use many different coping strategies. Our preliminary studies suggest that C16orf72 is a key in promoting the extreme stress tolerance of cancer cells. However, we do not yet know how exactly this protein works. By isolating C16orf72 from cells, we found that it binds to a protein called HUWE1. We plan to determine how these proteins cooperate. This should help us translate our findings into therapies. For example, we will map which specific parts of these two proteins interact. By defining this interface, we can design drugs to target it to reduce cancer cell resilience, and restore sensitivity to standard chemotherapies. We will also test the importance of this protein in a mouse model of tumorigenesis, where we will remove the gene that produces the protein from mouse cancer cells to test how these modified cancer cells form tumors (in the stressful environment of the animal, as opposed to in cancer cells in the laboratory grown under optimal conditions), and how they respond to a standard chemotherapy in this animal. In summary, our work will define a new way that cancer cells adapt to stress. The results will set the stage to design novel therapies that will be relevant to all types of cancer.