May 28, 2019
-- In a landmark study, scientists at the Agency for Science, Technology and Research's (A*STAR) Genome Institute of Singapore (GIS), Bioprocessing Technology Institute (BTI) and oncologists at the National Cancer Centre Singapore (NCCS), have discovered that cancer stem cells, the founder cells of a tumour, have unique nutrient requirements. Unlike the rest of the tumour cells, cancer stem cells are addicted to a type of dietary amino acid – methionine – which is linked to their ability to form tumours.
Methionine is an essential amino acid absorbed from diet for normal cell growth. However, a metabolite produced from it, S-adenosylmethionine (SAM), is involved in the regulation of critical gene functions in cancer stem cells. Importantly, this methionine metabolism pathway is controlled by a critical metabolic enzyme known as MAT2A (methionine adenoyltransferase 2A) that converts methionine to SAM.
This surprising discovery has implications on how one can develop better drugs against cancer. By specifically drugging this metabolic pathway, laboratory models of tumours are more effectively targeted compared to conventional treatment regimes. These findings were published online in the medical journal, Nature Medicine, on 06 May 2019. The research is supported by A*STAR, and the National Medical Research Council's Large Collaborative Grant for fighting lung cancer.
Cancer cases have been rising over the years. One in every four to five people in Singapore may develop cancer in their lifetime, and the number of people living with cancer will continue to increase. Tumours start from cancer stem cells. They are able to resist many forms of therapies, leading to the problem of resistance and relapse in patients. This has given rise to an urgent need for more precise methods to eliminate these recalcitrant cells. Through the integration of advanced genomics and metabolomics technologies housed at A*STAR, scientists are able to accurately pinpoint the unique nutritional requirements of cancer stem cells. This provides new insights and methods to avoid the problem of cancer resistance caused by cancer stem cells.
Dr Tam Wai Leong, the senior author of the study, Group Leader at the GIS and faculty member at Cancer Science Institute of Singapore, explained, "Cancer cells within a tumour are quite different from one another. Like human beings, they have different dietary preferences from each other. Through this study, we discovered that the cancer stem cells are addicted to a particular nutrient – methionine. By blocking the ability of the cancer stem cells to use this amino acid with potential anti-cancer therapeutics, we are able to effectively halt the growth of a tumour."
"MAT2A is an interesting enzyme that controls the metabolism of cancer cells. From our findings, this enzyme represents an important new drug target, as its inhibition led to the ablation of cancer stem cells. This paves the way for the development of next-generation drugs that target this dependence on methionine,"
said Dr Wang Zhenxun, the first author of this study.
Professor William Hwang, Medical Director at NCCS, said, "This important research provides key clinical insights on how oncologists can better overcome the problem of cancer resistance. The discovery of MAT2A as a new drug target may add to the arsenal of next generation anti-cancer drugs in our fight against cancer."
Professor Ng Huck Hui, Executive Director at GIS, said, "This is the first study demonstrating that cancer stem cells have unique dependencies on specific pathways. It also illuminates a way where we can exploit these dependencies to eliminate these cells from a tumour, thereby reducing the chance of cancer relapse and progression."