The human body is made up of more than 200 types of cell, from bone and brain to liver and lung. Each cell type is determined by the particular combination of proteins it produces. While skin cells are packed with a sturdy protein called keratin, for example, which gives them their structure, stomach cells produce powerful digestive enzymes to break down food.
Essential processes known as transcription and translation do not work properly in cancer cells, because they contain the wrong amounts and types of proteins. As a result, the cells do not function correctly and they grow out of control to form tumors.
With support from the Marie Curie International Outgoing Fellowship, the SOX project has spent two years studying the precise differences in translation between healthy and cancerous cells, and now aims to turn this knowledge into ideas for potential cancer treatments.
“For the last couple of decades, people have focused on transcription,” says researcher Ataman Sendoel, from the University of Zurich, Switzerland. “We have now learned that translation is as important as transcription in determining cell protein levels.”
Proteins are produced from recipes encoded within genes. When a particular protein needs to be made, the corresponding gene is ‘read’ to produce a molecular message known as RNA; this process is called transcription. Molecular ‘factories’ inside cells, called ribosomes, then use the instructions in the RNA to put together the correct protein – this is known as translation.
Sendoel’s work has focused on a common type of skin cancer known as squamous cell carcinoma, using mice as a model for the human disease. These cancers are driven by an overactive version of a gene called SOX2, which acts as a kind of ‘immortality factor’ enabling cells to keep growing and multiplying.
Using a technique called ribosome profiling, Sendoel studied exactly what happens when RNA is translated to make protein, looking for crucial differences in the process between healthy cells and squamous cell carcinoma.
He discovered that the ribosomes in the cancer cells switch to an alternative way of producing proteins. Rather than translating the correct RNA messages as they should, they start making unwanted proteins that are associated with cancer growth.
Looking closer, Sendoel found that the key difference lay in a protein called eIF2, which kick-starts the translation process in healthy cells. However, in the cancerous cells this molecule is replaced with an alternative version – known as eIF2A – which drives the production of rogue proteins.
“If we block this alternative protein production system, then cancers do not form at all,” explains Sendoel. “When we look at patients with squamous cell carcinoma of the head and neck, we find that people whose tumors have higher levels of eIF2A and more alternative protein production have a much shorter overall survival, suggesting that targeting this alternative translation programme could be a good strategy to treat cancer.”
Sendoel is now working on a screening technique to search for drugs that block eIF2A, which could form the basis of future cancer treatments. He is also investigating whether abnormal translation is involved in the growth of other types of cancer.
“We’re a long way from having a drug to use in the clinic and there are so many hurdles in between – but it’s definitely very exciting!”.