Age-induced accumulation of methylmalonic acid promotes tumour progression

Ana P. Gomes (), Didem Ilter, Vivien Low, Jennifer E. Endress, Juan Fernández-García, Adam Rosenzweig, Tanya Schild, Dorien Broekaert, Adnan Ahmed, Melanie Planque, Ilaria Elia, Julie Han, Charles Kinzig, Edouard Mullarky, Anders P. Mutvei, John Asara, Rafael Cabo, Lewis C. Cantley, Noah Dephoure, Sarah-Maria Fendt and John Blenis ()
Additional contact information
Ana P. Gomes: Weill Cornell Medicine
Didem Ilter: Weill Cornell Medicine
Vivien Low: Weill Cornell Medicine
Jennifer E. Endress: Weill Cornell Medicine
Juan Fernández-García: VIB-KU Leuven Center for Cancer Biology, VIB
Adam Rosenzweig: Weill Cornell Medicine
Tanya Schild: Weill Cornell Medicine
Dorien Broekaert: VIB-KU Leuven Center for Cancer Biology, VIB
Adnan Ahmed: Weill Cornell Medicine
Melanie Planque: VIB-KU Leuven Center for Cancer Biology, VIB
Ilaria Elia: VIB-KU Leuven Center for Cancer Biology, VIB
Julie Han: Weill Cornell Medicine
Charles Kinzig: Weill Cornell Medicine
Edouard Mullarky: Weill Cornell Medicine
Anders P. Mutvei: Weill Cornell Medicine
John Asara: Beth Israel Deaconess Medical Center and Harvard Medical School
Rafael Cabo: National Institute on Aging, National Institutes of Health
Lewis C. Cantley: Weill Cornell Medicine
Noah Dephoure: Weill Cornell Medicine
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology, VIB
John Blenis: Weill Cornell Medicine

Nature, 2020, vol. 585, issue 7824, 283-287

Abstract: Abstract The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1–6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9–12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.

Date: 2020
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DOI: 10.1038/s41586-020-2630-0

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