Department of Obstetrics and Gynecology/Section of Gynecologic Oncology-Center for Integrative Sciences, University of Chicago, Chicago, IL, USA.
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Metab. 2023 Sep;5(9):1563-1577. doi: 10.1038/s42255-023-00879-8. Epub 2023 Aug 31.
In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.
在肿瘤微环境中，脂肪细胞可以作为癌细胞的替代燃料来源。然而，脂肪细胞是否会影响癌细胞中的大分子生物合成尚不清楚。在这里，我们使用多平台代谢组学、成像质谱、同位素示踪和基因表达分析，系统地研究了原代人脂肪细胞与卵巢癌（OvCa）细胞之间的双向相互作用。我们报告称，在与脂肪细胞共培养的 OvCa 细胞中和转移瘤中，一部分来自糖酵解的葡萄糖用于甘油-3-磷酸（G3P）的生物合成。在常氧条件下，HIF1α 蛋白调节癌细胞中葡萄糖衍生碳的异常流动，导致甘油磷脂和三酰基甘油合成增加。HIF1α 或甘油磷酸酰基转移酶 3（甘油磷脂合成的调节酶）的敲低减少了 OvCa 异种移植模型中的转移。总之，我们表明，在富含脂肪的肿瘤微环境中，癌细胞将 G3P 作为关键膜和信号成分的前体生成，从而促进转移。针对富含脂肪的肿瘤微环境中特定的生物合成过程可能是一种有效的抗转移策略。
