细胞外基质
羟基化
癌细胞
利基
乳腺癌
化学
转移
生物化学
癌症研究
新陈代谢
细胞外
生物
代谢物
细胞生物学
癌症
酶
医学
内科学
作者
Ilaria Elia,Matteo Rossi,Steve Stegen,Dorien Broekaert,Ginevra Doglioni,Marit van Gorsel,Ruben Boon,Carmen Escalona-Noguero,Sophie Torrekens,Catherine M. Verfaillie,Erik Verbeken,Geert Carmeliet,Sarah-Maria Fendt
出处
期刊:Nature
[Springer Nature]
日期:2019-02-27
卷期号:568 (7750): 117-121
被引量:208
标识
DOI:10.1038/s41586-019-0977-x
摘要
The extracellular matrix is a major component of the local environment-that is, the niche-that determines cell behaviour1. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth2,3. However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen, because nutrients dictate which enzymatic reactions are active in cancer cells4,5. Here we show that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodelling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (P4HA). Inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast-cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodelling and the nutrient environment in the metastatic niche.
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