新型代谢基因特征簇作为乳腺癌干细胞生物标志物及其靶向的研究

Breast cancer stem cells (CSCs) with the capability of self-renewal, are critical to the tumor maintenance, growth and recurrence. How to accurately identify CSCs in tumors and effectively target them is a challenge in cancer treatment. Due to the heterogeneity of CSCs, currently used biomarkers for breast CSCs cannot completely cover all CSCs, and the specificity of identifying CSCs is also limited..Our preliminary data identified a specific metabolic gene signature associated with oxidative phosphorylation in breast CSCs. This gene signature provides a more complete assessment of the CSC subpopulation. Importantly, the upregulation of this gene signature was significantly correlated with recurrence and poor survival across various subtypes of breast cancer. Further studies have shown that metformin, a FDA approved clinical drug, can target oxidative phosphorylation and thus inhibit tumor stem cells. Based on these findings, this project will further study the metabolic gene signature as a biomarker of breast cancer stem cells at the level of cells, mice and patients, and evaluate its potential value in predicting chemotherapy resistance and prognosis of patients. At the same time, metformin was used to target tumor stem cells in combination with chemotherapy, so as to evaluate the effect of metformin on cancer stem cells in reversing drug resistance and prohibiting tumor recurrence.

乳腺癌干细胞（CSCs）是一类具有无限自我更新能力的肿瘤细胞，对肿瘤的维持、生长及转移、复发至关重要。如何准确完整识别肿瘤中CSCs及有效靶向是癌症治疗中的一个挑战。由于CSCs的异质性等原因，目前使用的乳腺癌CSCs生物标志物无法完全覆盖所有CSCs，而其识别CSCs的特异性也有限。.我们的前期工作发现乳腺癌CSCs中存在的一个特异性氧化磷酸化相关代谢基因特征簇。该特征簇能够广谱地覆盖多种亚型乳腺癌干细胞，并与乳腺癌患者预后呈正相关。进一步研究表明临床常用药二甲双胍能够靶向氧化磷酸化，从而抑制肿瘤干细胞。基于上述发现，本项目将进一步在细胞、小鼠以及患者多层次水平研究该代谢基因特征簇作为乳腺癌干细胞生物标志物，及预测患者化疗耐药、预后的潜在价值。同时，利用二甲双胍靶向肿瘤干细胞，与化疗联合使用，评估二甲双胍靶向肿瘤干细胞逆转肿瘤耐药及抑制肿瘤复发的作用，为其临床应用提供理论依据。

肿瘤干细胞在肿瘤发生、耐药、复发、转移等多个方面发挥至关重要的作用。杀死肿瘤干细胞被认为是有效治疗肿瘤的手段之一。肿瘤干细胞在肿瘤实体中只占极少部分，准确识别肿瘤干细胞对于深入了解肿瘤干细胞的生物学特征、功能，对肿瘤患者预后预测、治疗策略选择等都具有重要意义。此外，肿瘤干细胞的有效识别和生物特征的认识是靶向肿瘤干细胞的基础。.在本项目的资助下，我们利用临床肿瘤样本，结合二代测序、代谢测定、药物筛选等现代生物学方法鉴定了由氧化磷酸化相关基因组成的代谢基因特征簇作为广谱的乳腺癌干细胞生物标志物；该基因特征簇与与乳腺癌患者总生存率、无复发生存率、无转移生存率密切相关；进一步研究发现，利用二甲双胍靶向代谢基因特征簇能够有效抑制肿瘤干细胞生长；二甲双胍联合紫杉醇能够协调抑制化疗耐药肿瘤生长；阐明了细胞周期相关蛋白AURKB下调导致乳腺癌细胞化疗耐药的分子机制，并提出了靶向策略。研究成果有望为乳腺癌患者预后预测、肿瘤干细胞靶向、化疗耐药的治疗提供新的策略和思路。