Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
Nature. 2019 Apr;568(7750):117-121. doi: 10.1038/s41586-019-0977-x. Epub 2019 Feb 27.
The extracellular matrix is a major component of the local environment-that is, the niche-that determines cell behaviour. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth. 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. 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.
细胞外基质是局部环境（即小生境）的主要组成部分，它决定了细胞的行为。在转移生长过程中，癌细胞通过羟化胶原蛋白来促进自身的转移生长，从而塑造转移小生境中的细胞外基质。然而，只有特定的营养物质才能支持癌细胞羟化胶原蛋白的能力，因为营养物质决定了癌细胞中哪些酶促反应是活跃的。在这里，我们表明乳腺癌细胞依赖于营养物丙酮酸盐来驱动肺转移小生境中基于胶原蛋白的细胞外基质重塑。具体来说，我们发现丙酮酸盐摄取诱导α-酮戊二酸的产生。这种代谢物反过来通过增加酶胶原蛋白脯氨酰-4-羟化酶（P4HA）的活性来激活胶原蛋白羟化。抑制丙酮酸代谢足以损害胶原蛋白羟化，从而影响不同小鼠模型中乳腺癌衍生的肺转移的生长。总之，我们提供了一个机制上的理解，即胶原蛋白重塑与转移小生境中的营养环境之间的联系。
