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

Nature
Ilaria EliaSarah-Maria Fendt

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.

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Citations

Mar 21, 2019·Nature Reviews. Cancer·Ulrike Harjes
May 18, 2019·Cancers·Bo-Hyun Choi, Jonathan L Coloff
Oct 9, 2019·International Journal of Molecular Sciences·Mayra Paolillo, Sergio Schinelli
Jul 13, 2019·BMC Biology·Sarah-Maria Fendt
Sep 16, 2019·Journal of Translational Medicine·Shuaishuai XuLiang Liu
Aug 19, 2020·The FEBS Journal·Mattia D PizzagalliGiulio Superti-Furga
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Jun 20, 2019·The Journal of Experimental Medicine·Stephanie Houston
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May 10, 2019·Frontiers in Oncology·Ginevra DoglioniSarah-Maria Fendt
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Methods Mentioned

BETA
protein assay
PCR
Assay
flow cytometry

Software Mentioned

GraphPad Prism
ZEN blue
MATLAB
Imaris Image Analysis
MSD Chemstation Data Analysis
LAS AF
Agilent MassHunter
GNU Image Manipulation Program ( GIMP
GraphPad

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