杏吧原创

PANCREATIC cancer鈥檚 deadliest trick could be its undoing. Despite each person鈥檚 tumours having very different genetic mutations, they all cause the same metabolic changes that help it grow. What鈥檚 more, drugs already exist that can block the process.

Pancreatic cancer is the most lethal of all common cancers 鈥� 95 per cent of people die within five years of diagnosis. One reason it is so deadly is that no two cases are genetically the same. That means the tumour is more likely to evolve resistance to drugs, and that genomic studies aiming to find common mutations that could be targeted by treatment have fallen flat.

So and colleagues at the Garvan Institute of Medical Research in Sydney, Australia, tried a different approach. As well as looking for variations in the genome of different people鈥檚 tumours, they also looked at the biological processes at work in the cells.

To do this, they switched from using dead tumour cell samples to patient-derived tumour cell lines, in which fresh samples of a person鈥檚 tumour are grafted onto mice and grown to the required volumes. Growing them in animals makes for more lifelike tumours, and can produce large quantities of tissue for study.

This bank of living tumour cells allowed the team to study not only the genetics of the cells, but also how genetic mutations in the mitochondria 鈥� which drive energy production in the cell 鈥� caused changes in the cell鈥檚 metabolism.

To analyse the tumour cells鈥� metabolism, they used a technique called 鈥�metabolomics鈥�. This involves crushing live tumour cells and measuring the metabolites they contain using a mass spectrometer.

鈥淵ou can think of it like lines on a train map,鈥� says Saunders. 鈥淢etabolomics allows us to map those pathways and see which ones are switched on and switched off [in a cell].鈥�

Putting together their analyses of the mitochondrial DNA in each tumour cell line and the metabolic pathways at work, the team were able to deduce how each cell line鈥檚 genetics .

They found that pancreatic cancer cells consume not only glucose, as normal cells do, but also glutamine. This leads to the production of fatty acids 鈥� the building blocks of new cells 鈥� thereby allowing the tumours to proliferate wildly. 鈥淚nstead of using fuel for energy, they switch to using fuel to build new cells,鈥� Saunders says. The team presented its results at the in Australia last month.

This process has been seen before in other cancers, but this is the first time it has been shown to be involved in all pancreatic tumours, and that each tumour evolved different genetic mechanisms to do this.

The team was also able to see exactly how the cancers pulled off this trick. Each tumour they studied switched off the electron transport chain, which is involved in energy production. 鈥淭he cells in each tumour are finding a different way to do that,鈥� Saunders says. Since this happened in all 12 cell lines studied so far, each originating from a different tumour, Saunders suspects it鈥檚 the key change that makes pancreatic cancer so aggressive. The team now plan to genetically engineer healthy cells to produce the same metabolic behaviour. If those become cancerous, it will further prove the hypothesis.

The find offers enormous hope for treatment, says Saunders. There are drugs already . So it doesn鈥檛 matter that each person鈥檚 tumour might find different ways to switch the chain off, drugs ought to be able to reverse the process.

The team is already testing the drugs in the tumour cell lines it created. If all goes well, animal testing could start within six months, says Saunders.

Finding these similarities between the tumours offers new hope for treating a cancer which seemed too varied to target effectively, says Claudio Santos at . 鈥淪o perhaps in this age of cancer genomics showing how diverse and heterogenous human cancer is, we should be focusing on the common effects that different mutations lead to,鈥� he says.

This article appeared in print under the headline 鈥淧ancreatic cancer鈥檚 weak spot found鈥�