Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark; Department of Oncology, Odense University Hospital, 5000 Odense, Denmark; Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark.
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark.
Cell Rep. 2019 Jun 25;27(13):3927-3938.e6. doi: 10.1016/j.celrep.2019.05.104.
Tumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft tumors (PDXs) from ER breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNAi and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation, which could be rescued by a downstream metabolite. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target, as well as providing a mechanistic explanation for the therapeutic benefit of statins in breast cancer.
通过针对癌症干细胞（CSCs），肿瘤的清除率可能会大大提高，因为它们对常规治疗具有抗性。为了深入了解 CSCs 的独特生物学特性，我们从 ER 乳腺癌中分离出富含 CSCs 的肿瘤球体，从而开发出了源自患者的异种移植肿瘤（PDX）。我们对患者肿瘤组织和相应的 PDX 以及肿瘤球体进行了比较性的全蛋白质组分析。肿瘤球体表现出与从头胆固醇合成相关的蛋白表达增加。在一个大型乳腺癌队列中验证了胆固醇生物合成增加的临床相关性，表明其与无复发生存时间较短相关。胆固醇生物合成途径的 RNAi 和化学抑制减少了肿瘤球体的形成，而下游代谢物可挽救这种抑制作用。我们的研究结果表明，胆固醇生物合成途径是 CSC 增殖的核心，也是一个潜在的治疗靶点，并为他汀类药物在乳腺癌中的治疗益处提供了一种机制解释。
