The Biology of Lung Metastasis in Breast Cancer

乳腺癌肺转移的生物学

• 批准号: 10659152
• 负责人: Jonathan M. Backer
• 金额: $ 195.67万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659152
• 关键词: Affect; Animals; Area; Biology; Biosensor; Blood; Blood Platelets; Breast Cancer Cell; Cell Communication; Characteristics; Clinical; Clinical Treatment; Data; Disease; Distal; Environment; Epithelium; Event; Evolution; Extravasation; Flow Cytometry; Frequencies; Genetic Transcription; Genetic study; Growth; Human; Hypoxia; Image; Invaded; Investigation; Lead; Link; Lung; Macrophage; Mesenchymal; Metabolic; Metastatic Neoplasm to the Lung; Methodology; Neoplasm Circulating Cells; Neoplasm Metastasis; Oxidation-Reduction; PIK3CG gene; Positioning Attribute; Primary Neoplasm; Process; Proliferating; Property; Recording of previous events; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Site; Sorting; Stress; Stromal Cells; Techniques; Testing; Time; Tissues; Transcriptional Regulation; Visualization; analytical method; anticancer research; cell behavior; chemotherapy; clinical application; epithelial to mesenchymal transition; imaging modality; in vivo; inducible gene expression; innovation; insight; interest; lung colonization; lung imaging; lung metastatic; malignant breast neoplasm; metastatic process; mortality; multiphoton microscopy; neoplastic cell; new therapeutic target; novel; paracrine; programs; reconstruction; stem; stemness; synergism; tissue fixing; tool; tumor microenvironment

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.

转移是人类乳腺癌死亡的主要原因。原发性肿瘤的机制 微环境促进肿瘤细胞的侵袭和内渗已经被广泛研究。在 相反，调节远端部位血源性肿瘤细胞外渗的机制， 在新的微环境中生存和增殖，并重新传播到其他地点， 研究较少，也不太清楚。因此，对调节机制的研究 转移部位的乳腺癌细胞是具有重要临床意义的强烈科学兴趣的领域。 应用. CTC有效地散布在整个身体中，但以低频率形成转移。CTC， 成功外渗、存活和生长在远端部位获得了茎样特征， 这些过程。干细胞样特性的获得与上皮-间充质转化密切相关 （EMT）。因此，干细胞和EMT的转录控制是转移效率的重要调节因子。 干细胞和/或EMT由代谢、缺氧和氧化还原应激以及与细胞因子的相互作用诱导。 巨噬细胞和血小板。了解基质细胞对肿瘤细胞干细胞性的调节可能会导致 用于治疗转移性疾病的新治疗靶点的鉴定。 以前关于干细胞在远端转移中的作用的研究受到了分析的限制。 使用的方法。我们已经开发出突破性的新技术，使我们能够直接询问 干度与外渗效率、存活和体内生长之间的关系。我们的新型成像 方法联合收割机使用与多光子显微镜兼容的永久性肺成像窗口， 大视野的计算重建，以及新开发的生物传感器， 诱导干性、缺氧和ROS。这些工具允许乳腺癌细胞的可视化和分析 因为它们外渗并在肺中形成转移性集落。相比之下，传统的固定终点分析 组织不能提供关于干性在外渗和转移生长期间的作用的信息。 本项目围绕三个主要问题展开。首先，我们将定义信号通路， 调节肺转移小生境中的乳腺癌细胞。第二，我们将探索类茎的诱导 通过与基质细胞的相互作用，肿瘤细胞的性质，作为外渗和随后的关键调节剂， 肺部转移性生长第三，我们将寻求新的初步数据，化疗的影响， 转移部位利用项目和创新方法之间的重要协同作用 核心的进步，这个PPG是很好的定位，使我们的理解突破性的贡献 CTC外渗和在肺中生长，以及它们重新传播到三级部位。这些研究将 提供转移生物学的范式转变见解，对临床 治疗乳腺癌的全身转移性疾病。