MYC (pronounced Mick) is an oncogene – a gene that when deregulated can contribute to formation of cancer. Many things are known about the Myc protein produced from this gene: that it interacts with DNA to switch on/off many other genes (about 15% of all genes!), and in turn it orchestrates several (more than 10) cellular processes. But when there’s too much of it, it helps cancers to develop, and this is a key feature of more than half of all cancers in humans. But we still don’t know enough about it.
Scientists try to study MYC by “overexpressing” it in cells grown in the lab. These cells activate certain biosynthetic programmes that promote growth, but in turn the cells become more dependent on the nutrient amino acid glutamine. Glutamine is normally present in the body and is one of the nutrients that lab-folk feed to cells in experiments. Withdrawing glutamine from the cells causes them to stop growing and start dying, and understanding this process could give us new inroads to cancer treatment.
In this research form the Finch Lab, inspirational #bioscientists Dr Joy Edwards-Hicks and Dr Huizhong Su, and the rest of our diverse team discovered why this happens. Firstly, we found that when we withdraw glutamine and overexpress Myc, the cells are still trying to grow – make proteins, DNA, etc – so the fact they cannot grow could be a direct consequence of glutamine withdrawal, rather than some decision the cells are making in response. We found that there are several key molecules in the cells that build up, which is an indicator that certain biochemical pathways are blocked. Again, rather than this being a decision made by the cells, this must be either that they are running out of nutrients or running out of energy.
Finally, we figured out exactly what’s happening to the glutamine that we add to the cells. We did this by adding “heavy” nutrients to the cells, that have chemically identical atoms with a higher molecular weight, and measuring by mass-spectrometry which biomolecules these heavy atoms end up in. This enabled us to pinpoint the TCA Cycle, a core process in energy production, as the cause of Myc-induced glutamine sensitivity, indicating that the phenomenon is energetic in nature.
While this answer raises many more questions, it also leads to some specific therapeutic suggestions, like treating a cancer with drugs that alternately target synthesis to select for cells with higher energetic demand, and then target those energetic processes to selectively kill the cancer cells. The take-home?: our work shows that the energy-balance in cancer cells is a promising avenue in cancer research.
Find out more in this paper as published in Nature Communications “MYC sensitises cells to apoptosis by driving energetic demand” accessed via https://www.nature.com/articles/s41467-022-32368-z
Edwards-Hicks, J., Su, H., Mangolini, M. et al. MYC sensitises cells to apoptosis by driving energetic demand. Nat Commun 13, 4674 (2022). https://doi.org/10.1038/s41467-022-32368-z