The differential metabolic signature of breast cancer cellular response to olaparib treatment
The differential metabolic signature of breast cancer cellular response to olaparib treatment
复制标题
乳腺癌细胞对奥拉帕尼治疗反应的差异代谢特征
DOI：
10.1101/2022.06.14.495928
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Berardi D
中科院分区：
文献类型：
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作者：
Berardi D
乳腺癌仍然是全球女性癌症相关死亡率的主要原因。基因组稳定性丧失和细胞代谢失调是乳腺癌的公认特征，这为研究乳腺癌进展和化疗耐药性的驱动因素提供了机会。这项工作的首要目标是在一组乳腺癌细胞系中对奥拉帕尼治疗进行DNA损伤修复和细胞代谢的联合分析。通过应用结合非靶向代谢组学和分子生物学方法，我们的研究结果表明，从糖酵解到氨基酸利用的氨基酸代谢和代谢重编程失调是所有乳腺癌细胞系的共同特征，其中一些与临床乳腺癌肿瘤分析的结果一致。遗传改变的功能评估为设计新的预后工具提供了空间，并为新的化疗或药物组合的设计提供了信息。摘要代谢重编程和基因组不稳定性是癌症的关键标志，对其的综合分析最近受到欢迎。鉴于新出现的证据表明oncometalib在DNA损伤修复中的作用及其在乳腺癌治疗中的常规用途，现在是时候确定奥拉帕尼治疗对细胞代谢的影响。在这里，我们报告了具有DNA损伤修复缺陷的乳腺癌细胞系对奥拉帕尼暴露的生物分子反应。在乳腺癌细胞系中评估奥拉帕尼敏感性后，我们免疫探测DNA双链断裂灶，并使用基于非靶向质谱的代谢组学分析评估了不同奥拉帕尼治疗剂量下细胞代谢的变化。在鉴定改变的特征之后，我们进行了途径富集分析以测量响应奥拉帕尼治疗而发生的关键代谢变化。我们显示了对奥拉帕尼暴露的细胞系依赖性反应，以及对三阴性乳腺癌细胞系中DNA损伤灶积累的易感性增加。响应奥拉帕尼处理的代谢变化是细胞系和剂量依赖性的，其中我们主要观察到谷氨酰胺衍生的氨基酸和脂质代谢的代谢重编程。我们的工作证明了结合分子生物学和代谢组学研究对具有不同遗传特征的细胞系进行综合表征的有效性。需要进行后续研究来绘制乳腺癌细胞的基线代谢及其对药物治疗的独特反应。与基因组学和转录组学数据融合，这种读出可用于识别关键肿瘤，并为新药或化疗组合的设计提供依据。
Simple SummaryBreast cancer remains a leading cause of female cancer related mortality worldwide. Loss of genomic stability and dysregulation of cellular metabolism are well-recognized features of breast cancer, presenting an opportunity to study the drivers of breast cancer progression and resistance to chemotherapy. The overarching goal of this work is to perform combined analysis of DNA damage repair and cellular metabolism in response to olaparib treatment in a panel of breast cancer cell lines. By applying a combined untargeted metabolomics and molecular biology approach, our findings show dysregulation of amino acid metabolism and metabolic reprogramming from glycolysis to amino acid utilization to be a common feature in all breast cancer cell lines examined, some of which are consistent with findings from the analysis of clinical breast cancer tumours. Functional assessment of genetic alterations offers the scope to design new prognostic tools and inform the design of new chemotherapies or drug combinations.AbstractMetabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely to fingerprint the impact of olaparib treatment in cellular metabolism. Here, we report the biomolecular response of breast cancer cell lines with DNA damage repair defects to olaparib exposure. Following evaluation of olaparib sensitivity in breast cancer cell lines, we immunoprobed DNA double strand break foci and evaluated changes in cellular metabolism at various olaparib treatment doses using untargeted mass spectrometry-based metabolomics analysis. Following identification of altered features, we performed pathway enrichment analysis to measure key metabolic changes occurring in response to olaparib treatment. We show a cell-line-dependent response to olaparib exposure, and an increased susceptibility to DNA damage foci accumulation in triple-negative breast cancer cell lines. Metabolic changes in response to olaparib treatment were cell-line and dose-dependent, where we predominantly observed metabolic reprogramming of glutamine-derived amino acids and lipids metabolism. Our work demonstrates the effectiveness of combining molecular biology and metabolomics studies for the comprehensive characterisation of cell lines with different genetic profiles. Follow-on studies are needed to map the baseline metabolism of breast cancer cells and their unique response to drug treatment. Fused with genomic and transcriptomics data, such readout can be used to identify key oncometabolites and inform the rationale for the design of novel drugs or chemotherapy combinations.