Abstract
Pyruvate drives collagen hydroxylation in the extracellular matrix to support breast cancer metastasis.
Major finding: Pyruvate drives collagen hydroxylation in the extracellular matrix to support breast cancer metastasis.
Mechanism: Pyruvate-induced production of α-ketoglutarate metabolically activates prolyl 4-hydroxylase.
Impact: Targeting pyruvate uptake prevents collagen remodeling in the lung ECM and may impair metastatic growth.
Cancer cells promote metastatic outgrowth in part by inducing collagen hydroxylation to remodel the extracellular matrix (ECM) within the metastatic niche. Elia and colleagues investigated whether specific nutrients are required for cancer cell–mediated ECM remodeling, and found that depletion of pyruvate impaired the three-dimensional growth of breast cancer cells without affecting monolayer growth. Consistent with a role for this nutrient in collagen modification, pyruvate enhanced collagen hydroxylation and stability in breast cancer cells but not nontumorigenic cells, and this effect was abrogated by inhibition of the pyruvate transporter monocarboxylate transporter 2 (MCT2, also known as SLC16A7). Mechanistically, pyruvate uptake induced production of the metabolite α-ketoglutarate, which stimulated collagen hydroxylation by metabolically activating the enzyme collagen prolyl 4-hydroxylase (P4HA) in transformed cells; conversely, the addition of succinate, a coproduct of the P4HA enzymatic reaction, decreased the abundance of hydroxylated collagen. Of note, the metabolic regulation of P4HA by pyruvate was independent of the transcriptional regulation of P4HA by HIF1α. Furthermore, pyruvate-driven production of α-ketoglutarate was required for remodeling of the ECM in the lung metastatic niche in vivo; pharmacologic or genetic inhibition of MCT2 in two mouse models of breast cancer reduced collagen hydroxylation levels and suppressed lung metastasis, both of which were restored by concomitant treatment with α-ketoglutarate. These findings identify a critical role for pyruvate in the lung metastatic niche in mediating ECM modification by cancer cells to support metastatic outgrowth and suggest that targeted inhibition of pyruvate metabolism may impair lung metastasis by preventing aberrant collagen remodeling.
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