Targeting chemotherapy induced metabolic escape mechanisms to reduce cancer metastasis

癌症是欧洲和全世界的主要健康负担。虽然近几十年来在治疗原发性肿瘤方面取得了重大进展，但转移性癌症仍然与极低的生存率相关。提高对疾病基本机制的认识和相应的临床治疗方法的改进是克服这一未满足的临床需求的最有前途的方法。有趣的是，同时预期某些化疗方案促进转移。由于基因突变不能被确定为转移的唯一驱动因素，替代细胞适应机制，如蛋白质的翻译后修饰（PTM）进行了讨论。这种PTM的结构单元来源于细胞代谢。事实上，代谢改变是对化疗最敏感和最直接的细胞反应之一。因此，代谢与PTM和转移错综复杂地联系在一起。因此，如本项目所预期的，需要考虑所有这些方面的综合分析，以监测从化疗到转移的完整级联反应。具体而言，该项目研究了化疗诱导的中枢代谢结构单元乙酰辅酶A的改变及其与蛋白质乙酰化和随后的促转移信号传导的相关性。这种整体方法将确定和验证新的药理学干预点，以防止化疗后转移性肿瘤逃逸机制。为了获得所需的定量数据，该项目采用并扩展了可用的稳定同位素辅助的体外和体内通量分析工具以及其他组学方法，以将代谢改变与转移背景下的PTM联系起来。该项目通过将转移级联的各个方面与最先进的实验技术相结合，建立了一个优秀的培训框架。

Cancer is a major health burden in Europe and worldwide. While significant progress has been made in recent decades to treat primary tumors, metastatic cancer is still associated with devastatingly low survival rates. Enhanced understanding of the basic disease mechanisms and the according improvement of clinical treatment is the most promising approach to conquer this unmet clinical need. Intriguingly, it is meanwhile anticipated that certain chemotherapeutic regimens promote metastasis. As genetic mutations could not be identified as sole drivers of metastasis, alternative cellular adaptation mechanisms such as posttranslational modifications (PTMs) of proteins are discussed. Building blocks for such PTMs originate from cellular metabolism. In fact, metabolic alterations pose one of the most sensitive and immediate cellular responses to chemotherapy. Thus, metabolism is intricately linked to PTMs and metastasis. Consequently, a comprehensive analysis considering all these aspects, as intended in this project, is required to monitor the full cascade from chemotherapy to metastasis. Specifically, this project investigates chemotherapy induced alterations of the central metabolic building block acetyl-CoA and their relevance for protein acetylation and subsequent pro-metastatic signalling. This holistic approach will identify and validate novel pharmacologic intervention points to prevent metastatic tumor escape mechanisms upon chemotherapy. To obtain the required quantitative data, the project employs and extends available stable isotope-assisted in vitro and in vivo flux analysis tools and additional Omics approaches to link metabolic alterations to PTMs in the context of metastasis. This project sets an excellent training framework by combining individual aspects of the metastatic cascade with state-of-the-art experimental techniques.