An international partnership of cancer researchers, led by Dr Johannes Meiser and his team within the LIH’s Cancer Metabolism Group, has shown that targeting specific metabolic pathways in cancer cells can help to prevent them from spreading to other parts of the body. This could prove a major boost in the fight against a wide range of cancers whose ability to migrate and form secondary tumours continues to present a major stumbling block for conventional therapies..
The ability of cancers to metastasise (spread to new regions of the body) is one of the disease’s most dangerous features. Cancer cells that are able to survive conventional therapies and migrate to new regions often bare a developed resistance to further treatment, with the consequence that secondary tumours account for the majority of cancer deaths.
The most common drugs administered to treat cancer are currently used to target the cells and their ability to replicate, ideally slowing, preventing or even reversing tumour growth. Classical chemotherapy drugs for example, are designed to target the metabolism of cancer cells, interfering with the way they would normally produce needed components for proliferation such as proteins and lipids. The problem however, is that cancer cells that are persistent and slow to proliferate tend to be unaffected by these treatments and can travel to new regions of the body where they will gradually re-emerge as new tumours.
The question faced by Dr Meiser’s team at the LIH and their counterparts at the University of Luxembourg and the University of Glasgow, was whether targeting other metabolic pathways could affect the ability of such cancer cells to migrate away from the initial tumour site. In theory, this could effectively cripple the disease, preventing the occurrence of dangerous secondary tumours.
To carry out the investigation, the team focused on a specific metabolic pathway known as one-carbon (1C) metabolism, which is known to support various cellular actions and is spread across two main parts of the cell. This was a particularly promising target, as the commonly used chemotherapy drug Methotrexate (MTX), is known to inhibit this pathway and could be used as a tool to investigate how it works in more detail.
By using MTX, the researchers first found out that the drug only acts on one part of the 1C metabolism. With this new finding, they were able to discover two things. Firstly, that the affected part of 1C metabolism is important for cell proliferation but not for the cell’s ability to move to other sites (the cellular motility potential). Secondly, that the unaffected part of 1C metabolism does have an important effect on the cellular motility potential. This striking result meant that the team were subsequently able to inhibit tumour metastasis in a breast cancer model by targeting specific parts of 1C metabolism.
We show that inhibition of a specific part of 1C metabolism does not affect primary breast tumour growth but strongly inhibits metastasis to specific sites, like the lungs. We conclude that this part of 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential
summarises the study’s lead author Dr Nicole Kiweler from the LIH’s Department of Cancer Research.
Furthermore, with these promising results, Dr Meiser’s group plans to take the work even further. “Given previous workand the current study, there might also be differences when comparing migration with invasion [of cancer cells]. Ongoing work in our lab will help clarifying these questions in the future.”
The study was published recently in Nature Communications, a multidisciplinary journal of the renowned Nature Research group, under the full title “Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis” (DOI: 10.1038/natcommun/s41467-022-30363-y).
Johannes MeiserPrincipal Investigator, Head of Cancer Metabolism Group (FNR ATTRACT Fellow)
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