Age-induced accumulation of methylmalonic acid promotes tumour progression. Academic Article uri icon

Overview

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.

authors

  • Gomes, Ana P
  • Ilter, Didem
  • Low, Vi Vien
  • Endress, Jennifer E
  • Fernández-García, Juan
  • Rosenzweig, Adam
  • Schild, Tanya
  • Broekaert, Dorien
  • Ahmed, Adnan
  • Planque, Melanie
  • Elia, Ilaria
  • Han, Julie
  • Kinzig, Charles
  • Mullarky, Edouard
  • Mutvei, Anders P
  • Asara, John
  • de Cabo, Rafael
  • Cantley, Lewis C
  • Dephoure, Noah
  • Fendt, Sarah-Maria
  • Blenis, John

publication date

  • August 19, 2020

Research

keywords

  • Aging
  • Disease Progression
  • Methylmalonic Acid
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms

Identity

PubMed Central ID

  • PMC7785256

Scopus Document Identifier

  • 85089568623

Digital Object Identifier (DOI)

  • 10.1038/s41586-020-2630-0

PubMed ID

  • 32814897

Additional Document Info

volume

  • 585

issue

  • 7824