In the ever-evolving war against cancer, understanding the enemy’s strategy is vital for developing effective treatments. According to recent research published in ‘Nature Medicine’, scientists may have identified a metabolic vulnerability in the most defiant cancer cells known as tumor-initiating cells (TICs). This discovery could pave the way for revolutionary therapies targeting these stubborn cells that often lead to cancer recurrence and are resistant to conventional treatments.

The groundbreaking study led by an international team of researchers, including prominent figures like Wang Zhenxun, Yip Lian Yee, and Tam Wai Leong from the Agency for Science, Technology and Research (A*STAR), Singapore, draws a bright spotlight on methionine, an amino acid that TICs seemingly can’t live without. Their findings, which reveal the heightened activity of the methionine cycle in TICs, might hold the key to crippling these cells and halting cancer progression.

DOI: 10.1038/s41591-019-0423-5

Key Insights into Tumor-Initiating Cells’ Addiction to Methionine

In their study, published in May 2019 with subsequent updates leading into March 2020, the researchers embarked on a journey to decode the metabolic peculiarities of TICs. By performing comprehensive metabolomic analyses and tracing the journey of metabolites within these cells, they observed a significantly elevated activity of the methionine cycle.

The methionine cycle plays a critical role in various cellular processes, primarily through its involvement in epigenetic regulation and protein synthesis. Its heightened activity in TICs indicated an unusual dependency, bordering on addiction, as these cells consumed exogenous methionine voraciously, unable to regenerate sufficient amounts on their own.

Targeting the Methionine Cycle: A New Cancer Therapy?

The study highlighted that MAT2A, an enzyme critical in the methionine cycle, might be the mastermind behind this dependency. These TICs heavily relied on MAT2A for their methionine cycle activity and transmethylation rates. The intriguing aspect of this discovery was the realization that pharmacologically inhibiting the methionine cycle could effectively incapacitate the TICs, impairing their tumor-initiating capabilities.

This revelation has substantial implications for cancer treatment strategies. While many therapies tend to target rapidly dividing cells, they often miss the mark with TICs, which can lie dormant and are capable of evading treatment, only to later cause relapse. By targeting their metabolic cravings for methionine, there’s potential to craft novel therapies that could prevent recurrence and improve patient outcomes.

Epigenetics and Metabolism: A Link That Defines Cancer’s Onset

The scientists also found that the influence of methionine cycle flux extended beyond mere metabolism, directly impacting the cancer cells’ epigenetic state. These changes in the epigenetic landscape are crucial to understanding how TICs maintain their potency and ability to initiate tumors.

In this context, methionine’s role becomes two-fold. Firstly, as a building block for proteins, it is vital for cell growth and proliferation. Secondly, it’s a donor for methyl groups required for epigenetic modifications, like DNA methylation, which can turn genes on or off without altering the DNA sequence. The study suggests that the aberrant methionine cycle in TICs significantly contributes to establishing a permissive epigenetic state for tumor initiation.

Broader Implications for Diverse Cancer Types

Looking beyond TICs, the researchers also identified that the methionine cycle enzymes, including MAT2A, are enriched across different tumor types. The expression levels of these enzymes had a direct correlation with the sensitivity of certain cancer cells to therapeutic inhibition. Consequently, MAT2A could serve as a biomarker for identifying cancers most likely to respond to a therapy targeting the methionine cycle.

The research team postulates that methionine metabolic pathways could be universal Achilles’ heels for a wide range of cancers. This opens up possibilities for a multi-pronged attack against various forms of cancer, with methionine deprivation strategies potentially being a unifying element.

Keywords

1. Methionine
2. Cancer Therapy
3. Tumor-Initiating Cells
4. Metabolic Dependency
5. MAT2A Inhibition

References

1. Wang, Z., et al. (2019). Methionine is a metabolic dependency of tumor-initiating cells. Nature Medicine, 25(5), 825-837. DOI: 10.1038/s41591-019-0423-5
2. Lu, S. C. (2009). Regulation of glutathione synthesis. Molecular aspects of medicine, 30(1-2), 42-59.
3. Pavlova, N. N., & Thompson, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell metabolism, 23(1), 27-47.
4. Kornberg, M. D., et al. (2018). Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nature Reviews Cancer, 18(11), 629-643.
5. Locasale, J. W. (2013). Serine, glycine and one-carbon units: cancer metabolism in full circle. Nature Reviews Cancer, 13(8), 572-583.

In conclusion, the findings of this study not only provide insight into the metabolic lifeblood of TICs but also cast methionine cycle targeting as a promising avenue for anti-cancer therapies. With further research and clinical trials, we stand on the cusp of a new era in the targeting of these resilient cells. Importantly, this study underscores the fundamental relationship between cellular metabolism and the origins of cancer, placing metabolism at the forefront of oncological research and treatment design.

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Last Update: February 10, 2024