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Breast cancer cells rely on environmental pyruvate to shape the metastatic niche
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Journal Article
Breast cancer cells rely on environmental pyruvate to shape the metastatic niche
2019
Overview
The extracellular matrix is a major component of the local environment—that is, the niche—that determines cell behaviour
1
. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth
2
,
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 cells
4
,
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.
Exogenous pyruvate is needed for breast cancer cells to form metastases, and the inhibition of pyruvate metabolism impairs collagen hydroxylation and the growth of lung metastases in different mouse models.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 42/44
/ 631/45
/ 64/60
/ 82/58
/ Animals
/ Breast Neoplasms - enzymology
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cancer
/ Carbon
/ Collagen
/ CRISPR
/ Enzyme Activation - drug effects
/ Enzymes
/ Extracellular Matrix - drug effects
/ Extracellular Matrix - metabolism
/ Female
/ Humanities and Social Sciences
/ Humans
/ Hydroxylation - drug effects
/ Ketoglutaric Acids - metabolism
/ Letter
/ Mice
/ Neoplasm Metastasis - pathology
/ Procollagen-Proline Dioxygenase - metabolism
/ Science
/ Tumor Microenvironment - drug effects
/ Tumors
