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Age-induced accumulation of methylmalonic acid promotes tumour progression

机译：年龄诱导的甲基丙醇积累促进肿瘤进展

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摘要

Ageing in humans is associated with an increase in circulating methylmalonic acid, which induces expression of SOX4 and promotes tumour progression.The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards(1-6). Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy(2,3,7,8). 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 ageing(9-12). 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.
机译：人类衰老与循环甲基羟基丙酸的增加有关，其诱导SOX4的表达并促进肿瘤进展。癌症和相关死亡率的风险从65岁开始的人类大致增加（1-6）。尽管如此，我们对年龄和癌症之间复杂关系的理解仍处于初期（2,3,7,8）。几十年来，该联系在很大程度上归因于增加老年人诱变的暴露时间。然而，这种观点不考虑饮食，运动和靶向代谢衰老速度（9-12）的饮食的既定作用。在这里，我们表明年龄发生的代谢改变可以产生有利于肿瘤进展和侵略性的系统性环境。具体而言，我们表明甲基羟基丙酸（MMA）是丙酸酯代谢的副产物，在老年人的血清中上调，用作肿瘤进展的介质。我们将其追溯到MMA诱导SOX4表达的能力，从而引发可引发患有侵袭性质的癌细胞的转录重编程。因此，MMA的积累代表了老化和癌症进展之间的联系，表明MMA是晚期癌症的有希望的治疗靶标。

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  • 来源
    《Nature》 |2020年第7824期|283-287|共5页
  • 作者

    Gomes Ana P.; Ilter Didem; Low Vivien; Endress Jennifer E.; Fernandez-Garcia 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;

  • 作者单位

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Pharmacol New York NY 10065 USA|H Lee Moffitt Canc Ctr & Res Inst Dept Mol Oncol Tampa FL 33612 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Pharmacol New York NY 10065 USA|H Lee Moffitt Canc Ctr & Res Inst Dept Mol Oncol Tampa FL 33612 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Biochem Struct Dev Cell & Mol Biol Allied PhD Pro New York NY USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Biochem Struct Dev Cell & Mol Biol Allied PhD Pro New York NY USA;

    VIB VIB KU Leuven Ctr Canc Biol Lab Cellular Metab & Metab Regulat Leuven Belgium|Katholieke Univ Leuven Dept Oncol Lab Cellular Metab & Metab Regulat Leuven Belgium|Leuven Canc Inst LKI Leuven Belgium;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Pharmacol New York NY 10065 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Biochem Struct Dev Cell & Mol Biol Allied PhD Pro New York NY USA;

    VIB VIB KU Leuven Ctr Canc Biol Lab Cellular Metab & Metab Regulat Leuven Belgium|Katholieke Univ Leuven Dept Oncol Lab Cellular Metab & Metab Regulat Leuven Belgium|Leuven Canc Inst LKI Leuven Belgium;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Biochem New York NY 10065 USA;

    VIB VIB KU Leuven Ctr Canc Biol Lab Cellular Metab & Metab Regulat Leuven Belgium|Katholieke Univ Leuven Dept Oncol Lab Cellular Metab & Metab Regulat Leuven Belgium|Leuven Canc Inst LKI Leuven Belgium;

    VIB VIB KU Leuven Ctr Canc Biol Lab Cellular Metab & Metab Regulat Leuven Belgium|Katholieke Univ Leuven Dept Oncol Lab Cellular Metab & Metab Regulat Leuven Belgium|Leuven Canc Inst LKI Leuven Belgium;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Pharmacol New York NY 10065 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Rockefeller Univ Weill Cornell Med Sloan Kettering Triinst MD PhD Program 1230 York Ave New York NY 10021 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Med New York NY USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Pharmacol New York NY 10065 USA;

    Beth Israel Deaconess Med Ctr Dept Med Boston MA 02215 USA|Harvard Med Sch Boston MA 02115 USA;

    NIA Lab Expt Gerontol NIH Baltimore MD 21224 USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Med New York NY USA;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Biochem New York NY 10065 USA;

    VIB VIB KU Leuven Ctr Canc Biol Lab Cellular Metab & Metab Regulat Leuven Belgium|Katholieke Univ Leuven Dept Oncol Lab Cellular Metab & Metab Regulat Leuven Belgium|Leuven Canc Inst LKI Leuven Belgium;

    Weill Cornell Med Meyer Canc Ctr New York NY 10065 USA|Weill Cornell Med Dept Pharmacol New York NY 10065 USA|Weill Cornell Med Dept Biochem New York NY 10065 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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