New mechanisms discovered in identification of cancer growth

New mechanisms discovered in identification of cancer growth

A team of researchers have discovered new mechanisms which help to understand the growth and treatment of colorectal cancer.

As part of a Cancer Research UK Grand Challenge, the Rosetta Programme researchers have studied a particular and common genetic subtype of colon cancer and have discovered important mechanisms which help to understand how this type of cancer is able to grow. The study has the potential to be transformative to a treatment refractory patient population.

The Rosetta Programme is led by Professor Josephine Bunch at the National Physical Laboratory (NPL) and this particular study, undertaken by the Rosetta team, was led by Professor Owen Sansom at the Cancer Research UK Beatson Institute and the University of Glasgow.

The application of ‘metabotyping’

The mechanisms discovered by the team have provided new ideas about how to treat this type of cancer after identifying 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, as well as being a pressing clinical issue in colorectal cancer.

To date, 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 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 has 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.

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.”

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