The Biology of Lung Metastasis in Breast Cancer

转移是导致人类乳腺癌死亡的主要原因。原发肿瘤的发病机制 微环境促进肿瘤细胞的侵袭和侵袭已经得到了广泛的研究。在……里面 相比之下，调控远端部位血源性肿瘤细胞外渗的机制，其 在新的微环境中生存和繁殖，并重新传播到更多的地点， 研究较少，也不能很好地理解。因此，对调控机制的研究 转移部位的乳腺癌细胞是一个具有重要临床意义的研究领域。 申请。 CTC有效地扩散到全身，但形成转移的频率很低。CTC 在远端部位成功渗出、存活和生长获得了类似茎的特征，促进了 这些过程。干细胞样属性的获得与上皮-间充质转化密切相关 (EMT)。因此，干性和EMT的转录调控是转移效率的重要调节因素。 茎和/或EMT是由代谢、低氧和氧化还原应激以及与 巨噬细胞和血小板。了解基质细胞对肿瘤细胞干细胞的调节可能导致 寻找治疗转移性疾病的新靶点。 以前关于干细胞在转移到远端部位中的作用的研究受到分析性的显著限制 使用的方法。我们已经开发出突破性的新技术，使我们能够直接审问 茎长与体内渗出、存活和生长效率的关系。我们的新成像技术 方法结合使用与多光子显微镜兼容的永久性肺成像窗口，新颖 大视野的计算重建，以及新开发的生物传感器 茎的诱导、低氧和ROS。这些工具允许可视化和分析乳腺癌细胞 当它们渗出并在肺内形成转移菌落时。相比之下，传统的固定终点分析 组织不能提供有关茎在渗出和转移生长过程中的作用的信息。 本计划项目围绕三个主要问题进行组织。首先，我们将定义信号通路， 调节乳腺癌细胞在肺转移的利基。第二，我们将探索茎状细胞的诱导 肿瘤细胞与基质细胞相互作用的性质，作为渗出和随后的关键调节因子 肺部转移性生长。第三，我们将寻求有关化疗效果的新的初步数据。 转移部位。利用项目和创新方法之间的重要协同作用 在核心的推动下，这一PPG处于有利地位，将为我们的理解做出开创性的贡献 四氯化碳的渗出和在肺中生长，以及它们重新扩散到第三级站点。这些研究将 提供对转移生物学的范式转换的见解，对临床具有重要的意义 乳腺癌全身转移性疾病的治疗。

Metastasis is the major cause of mortality in human breast cancer. The mechanisms by which the primary tumor microenvironment promotes the invasion and intravasation of tumor cells has been extensively studied. In contrast, the mechanisms regulating extravasation of blood-borne tumor cells at distal sites, their survival and proliferation in their new microenvironment, and their re-dissemination to additional sites, are less studied and not well understood. Therefore, the investigation of the mechanisms that regulate breast cancer cells at the metastatic site are an area of intense scientific interest with important clinical applications. CTCs efficiently disseminate throughout the body but form metastases with low frequency. The CTCs that successfully extravasate, survive and grow at distal sites have acquired stem-like characteristics that promote these processes. The acquisition of stem-like properties is closely linked to the epithelial-mesenchymal transition (EMT). Thus, the transcriptional control of stemness and EMT is an important regulator of metastatic efficiency. Stemness and/or EMT is induced by metabolic, hypoxic and redox stress, as well as by interactions with macrophages and platelets. Understanding the regulation of tumor cell stemness by stromal cells could lead to the identification of novel therapeutic targets for the treatment of metastatic disease. Previous studies on the role of stemness in metastasis to distal sites has been significantly limited by the analytic methods used. We have developed ground-breaking new techniques that allow us to directly interrogate the relationship between stemness and the efficiency of extravasation, survival and growth in vivo. Our novel imaging methods combine the use of a permanent lung imaging window compatible with multiphoton microscopy, novel computational reconstructions of large fields of view, and newly developed biosensors that report on the induction of stemness, hypoxia and ROS. These tools allow the visualization and analysis of breast cancer cells as they extravasate and form metastatic colonies in the lung. In contrast, traditional end-point analyses of fixed tissues cannot provide information on the role of stemness during extravasation and metastatic growth. This Program Project is organized around three major questions. First, we will define the signaling pathways that regulate breast cancer cells in the lung metastatic niche. Second, we will explore the induction of stem-like properties in tumor cells by interactions with stromal cells, as a critical regulator of extravasation and subsequent metastatic growth in the lung. Third, we will pursue novel preliminary data on the effects of chemotherapy in the metastatic site. Taking advantage of important synergies between the Projects and innovative methodological advances by the Cores, this PPG is well-positioned to make ground-breaking contributions to our understanding of CTC extravasation and grow in the lung, as well as their re-disseminate to tertiary sites. These studies will provide paradigm-shifting insights into the biology of metastasis, with important implications for the clinical treatment of systemic metastatic disease in breast cancer.