Extracellular matrix (ECM) is a major component of the local environment, i.e. the niche, that can determine cell behavior 1 . During metastatic growth, cancer cells shape the ECM 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 discovered that breast cancer cells rely on the nutrient pyruvate to drive collagen-based ECM remodeling in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activated collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (P4HA). Strikingly, 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 remodeling and the nutrient environment in the metastatic niche.
Metastasis to distant organs is a predictor of poor prognosis. Therefore, it is of paramount importance to understand the mechanisms that impinge on the different steps of the metastatic cascade. Recent work has revealed that particular metabolic pathways are rewired in cancer cells to support their transition through the metastatic cascade, resulting in the formation of secondary tumors in distant organs. Indeed, metabolic rewiring induces signaling pathways during initial cancer invasion, circulating cancer cells depend on enhanced antioxidant defenses, and cancer cells colonizing a distant organ require increased ATP production. Moreover, the local environment of the metastatic niche dictates the metabolic pathways secondary tumors rely on. Here we describe mechanisms of metabolic rewiring associated with distinct steps of metastasis formation.
Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.
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