Breast cancer cells rely on environmental pyruvate to shape the metastatic niche

Ilaria Elia, Matteo Rossi, Steve Stegen, Dorien Broekaert, Ginevra Doglioni, Marit van Gorsel, Ruben Boon, Carmen Escalona-Noguero, Sophie Torrekens, Catherine Verfaillie, Erik Verbeken, Geert Carmeliet and Sarah-Maria Fendt ()
Additional contact information
Ilaria Elia: VIB-KU Leuven Center for Cancer Biology, VIB
Matteo Rossi: VIB-KU Leuven Center for Cancer Biology, VIB
Steve Stegen: Metabolism and Ageing, KU Leuven
Dorien Broekaert: VIB-KU Leuven Center for Cancer Biology, VIB
Ginevra Doglioni: VIB-KU Leuven Center for Cancer Biology, VIB
Marit van Gorsel: VIB-KU Leuven Center for Cancer Biology, VIB
Ruben Boon: Stem Cell Institute, KU Leuven
Carmen Escalona-Noguero: VIB-KU Leuven Center for Cancer Biology, VIB
Sophie Torrekens: Metabolism and Ageing, KU Leuven
Catherine Verfaillie: Stem Cell Institute, KU Leuven
Erik Verbeken: KU Leuven
Geert Carmeliet: Metabolism and Ageing, KU Leuven
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology, VIB

Nature, 2019, vol. 568, issue 7750, 117-121

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-0977-x

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