The metabolism of breast cancer metastasis to the lung: Key pathways and their implications in the metastatic microenvironment.

转移仍然是大多数与癌症相关的死亡的原因。因此，迫切需要改进对最具侵袭性的癌症类型的治疗，例如三阴性乳腺癌。代谢适应正在成为专门针对转移过程的标志。根据我们的初步数据，乳腺癌转移到肺部的代谢特征包括蛋氨酸循环上调、谷胱甘肽生物合成和对细胞外半胱氨酸的依赖。然而，这些途径之间的相互联系以及它们在肺部定植过程中所起的作用仍不清楚。此外，肺微环境中肿瘤细胞和邻近细胞之间的代谢串扰也没有明确的定义。因此，本项目的第一个目标是探索蛋氨酸和半胱氨酸通路在乳腺转移细胞中的功能作用，并确定可能的代谢靶点。其次，我的目标是在肺微环境的背景下研究已定义的适应。为了实现这一点，我将使用体内和体外Myc诱导的乳腺癌小鼠模型。转移细胞的代谢脆弱性将使用稳定同位素分解的代谢组学、基因工程工具和药理学干预进行评估。然后，将使用一种独特的方法来定义肺微环境中的代谢相互作用，该方法结合了新的技术，如质谱仪成像、成像质量细胞术和单细胞RNA测序。总体而言，这项工作的意义将是发现新的转移代谢机制，最终有助于设计更有效的乳腺癌转移治疗方法。

Metastasis is still responsible for the majority cancer-related deaths. Consequently, there is an urgent need to improve the treatment for the most aggressive cancer types, such as triple negative breast cancer. Metabolic adaptation is emerging as a hallmark to specifically target the metastatic process. According to our preliminary data, the metabolic features of breast cancer metastasis to the lungs include the upregulation of the methionine cycle, glutathione biosynthesis and a dependence on extracellular cystine. However, the interconnections between these pathways and the role they play in the lung colonisation process remain unclear. Also, the metabolic crosstalk between tumour cells and neighbouring cells in the lung microenvironment is poorly defined. Therefore, the first objective of this project is to explore the functional role of methionine and cysteine pathways in the breast metastatic cells and identify possible metabolic targets. Secondly, I aim to study the defined adaptations in the context of the lung microenvironment. To achieve that, I will use in vivo and ex vivo Myc-induced breast cancer mouse model. The metabolic vulnerabilities of the metastatic cells will be assessed using stable isotope-resolved metabolomics, genetic engineering tools and pharmacological interventions. Then, the metabolic interactions in the lung microenvironment will be defined using a unique approach that combines novel techniques such as mass spectrometry imaging, imaging mass cytometry, and single-cell RNA sequencing. Overall, the implications of this work will be the discovery of new metabolic mechanisms of metastasis that eventually contribute to the design of more efficient therapeutic approach for breast metastatic cancer.