Biomedical Engineering, Boston University, Boston, MA, 02155, USA.
Electrical and Computer Engineering, Boston University, Boston, MA, 02155, USA.
Nat Commun. 2022 Aug 5;13(1):4554. doi: 10.1038/s41467-022-32101-w.
Increased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors.
糖酵解增加被认为是癌症的一个标志。然而，治疗耐药性发展过程中癌细胞代谢重编程的研究还很不足。在这里，我们通过高通量受激拉曼散射成像和单细胞分析发现，顺铂耐药细胞表现出增加的脂肪酸 (FA) 摄取，伴随着葡萄糖摄取和脂肪生成减少，表明从葡萄糖到 FA 依赖的合成代谢和能量代谢的重编程。一个包含葡萄糖衍生的合成代谢和 FA 摄取的代谢指标与卵巢癌细胞 (OC) 系和原代细胞中顺铂耐药的水平呈线性相关。增加的 FA 摄取通过增强β氧化，促进了在顺铂诱导的氧化应激下癌细胞的存活。因此，用小分子抑制剂阻断β氧化与顺铂或卡铂联合使用，在体外协同抑制 OC 的增殖，并在体内抑制患者来源的异种移植瘤的生长。总的来说，这些发现为在单细胞水平上快速检测顺铂耐药性提供了支持，并为治疗顺铂耐药肿瘤提供了一种策略。
