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Important mechanisms discovered in identification of cancer growth

The new discoveries have been made by the Rosetta Programme team, as part of a CRUK Grand Challenge

A multidisciplinary consortium, as part of a Cancer Research UK Grand Challenge, has made new discoveries about growth and treatment of colorectal cancer. The Rosetta Programme, led by Professor Josephine Bunch at NPL brings together international and multidisciplinary chemists, physicists, data scientists and biologists, using the best imaging techniques to understand cancer. This study, undertaken by the Rosetta team, was led by Professor Owen Sansom at the Cancer Research UK Beatson Institute and the University of Glasgow.

Identifying clinically relevant targets for new drugs to fight diseases such as cancer is a key element in the design and development of novel treatment approaches. The team has studied a particular and common genetic subtype of colon cancer, using well defined genetically engineered models and metabolic imaging approaches including mass spectrometry imaging.

The team have discovered important mechanisms which help to understand how this type of cancer is able to grow. Importantly, these mechanisms identified also provide new ideas about how to treat this type of cancer.

The new findings from the team have identified the role of SLC7A5 in KRAS-driven colorectal cancer. The three human RAS genes, KRAS, NRAS and HRAS, are the most frequently mutated oncogenes in human cancer. Mutant KRAS is very common, found in up to 45% of colorectal cancers, and is usually associated with poorer survival and increased tumour aggressiveness.

KRAS mutation in colorectal cancer is a pressing clinical issue. Targeting the differential metabolic vulnerabilities of KRAS-mutant cancers has failed to translate clinically, primarily due to the inability of cultured cells to recapitulate the metabolic dependencies of complex heterogeneous tumours.

The team have identified a single metabolic target, SLC7A5, which is critical for growth and spread of metabolically defined KRAS mutant colorectal cancer and sensitises to clinically relevant therapeutics.

It’s been known for some time that mutant KRAS alters the metabolic dependencies of cancer cells, rendering them ‘addicted’ to the metabolite glutamine. Using a combination of models, the team have proven that although glutamine is important for the spread of colorectal tumour cells, it does not have a direct role in the cell growth. It is ejected from the cell by the antiporter SLC7A5, which simultaneously pulls in a range of other metabolites from surrounding tissue.

This study has the potential to be transformative to a treatment refractory patient population. Finding a way to target SLC7A5, could provide the opportunity to target KRAS-mutant colorectal cancer cells. 

The application of ‘metabotyping’ approaches will now be used in clinical samples to align patient groups to SLC7A5 dependent metabolic programmes.

Professor Josephine Bunch, NPL Fellow, Science Area Leader in National Centre of Excellence in Mass Spectroscopy Imaging and leader of the Rosetta programme, states: “These exciting results show the power of using sensitive, untargeted imaging methods to examine extremely complex tissues. Here we were able to support the Beatson team to detect and image key metabolites such as glutamine, directly in tumours using a mass spectrometry imaging. Providing spatially resolved measurements of these metabolites have allowed them to elucidate key mechanisms involved in KRAS-mutant forms of colon cancer, providing new ideas for future therapeutic strategies.”

Professor Owen Sansom at the Cancer Research UK Beatson Institute and the University of Glasgow states: “For many years we have known that cancer cells that carry KRAS mutation alter their metabolism (energy requirements). Here, through our grand challenge Rosetta team, we were able to visualise metabolism in tumours and see that there are key amino acids that are required for the growth of KRAS mutant colorectal cancers.  Importantly, removing a key amino acid transporter SLC7A5, we could stop the growth of these tumours. Given KRAS mutant colorectal cancers are hard to treat we are excited that developing new therapies to target SLC7A5 could in the future be efficacious for CRC.”

Read the article here in Nature Genetics.

15 Jan 2021