Targeting chemotherapy induced metabolic escape mechanisms to reduce cancer metastasis

靶向化疗诱导的代谢逃逸机制以减少癌症转移

• 批准号: 447238381
• 负责人: Dr. Nicole Kiweler, Ph.D.
• 金额: --
• 依托单位: NORLUX Neuro-Oncology Laboratory
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/447238381?language=en
• 关键词: Targeting; chemotherapy; induced; metabolic; escape

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.

癌症是欧洲和世界范围内的主要健康负担。虽然近几十年来在治疗原发肿瘤方面取得了重大进展，但转移性癌症仍然与极低的存活率有关。加强对基本发病机制的了解，并相应改进临床治疗，是克服这一未得到满足的临床需求的最有希望的途径。有趣的是，同时预计某些化疗方案会促进转移。由于基因突变不能被确定为转移的唯一驱动因素，本文讨论了其他细胞适应机制，如蛋白质的翻译后修饰(PTM)。这类PTM的构件来自细胞新陈代谢。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PTMS和转移有着错综复杂的联系。因此，正如本项目所希望的那样，需要考虑所有这些方面的全面分析，以监测从化疗到转移的整个级联过程。具体地说，该项目调查了化疗引起的中央代谢构建块乙酰辅酶A的变化及其与蛋白质乙酰化和随后的促转移信号的相关性。这一整体方法将确定和验证新的药物干预点，以防止化疗中转移的肿瘤逃逸机制。为了获得所需的定量数据，该项目采用并扩展了现有的稳定同位素辅助的体外和体内通量分析工具和附加的Omics方法，以将代谢变化与转移情况下的PTM联系起来。该项目通过将转移级联的个别方面与最先进的实验技术相结合，建立了一个极好的培训框架。