Systemic regulation of metastasis

项目摘要 癌症是一种系统性疾病。它的生长和恶性进展不仅依赖于内在的异常 肿瘤细胞的遗传和表观遗传组成，也对肿瘤诱导的全身因素产生影响 在本地和远程微环境中的细胞。重要的是，肿瘤之间存在动态串扰- 受过教育的组织和器官以及肿瘤本身，尤其是在转移过程中。就像肿瘤一样 重塑其局部微环境，诱使其支持癌症生长，它施加全身效应，征服 免疫系统和远处器官，不仅导致转移，而且还导致血管变化(血管 渗漏、凝血)、肌肉和代谢改变(恶病质)、肝和肺衰竭、骨骼改变 密度(骨质疏松症或骨化症)和神经疾病，但最重要的可能是炎症和免疫 压制。肿瘤发挥其全身作用，诱使宿主的各种器官系统支持 肿瘤生长通过肿瘤分泌因子，如可溶性因子(细胞因子和趋化因子)和 外体(和外体，我们最近发现的新粒子)纳米胶囊，携带复杂的货物， 包括蛋白质、代谢物、DNA和编码以及非编码RNA。有效的发展 抗转移治疗的基础是我们对这些迭代和复杂的相互作用的理解 肿瘤和它的宿主之间的联系，以及想办法中断这种交流。我们开发了小说 分析肿瘤来源的外切体和外切体的异质性和功能作用的方法 转移以及它们引起全身变化的能力。最终，我们建议探索 抑制造血细胞中特定的外切体货物分子或其靶标的可能性可能 逆转免疫抑制、转移前的生态位形成和癌症的全身效应。总而言之， 我们将重点研究外切体和外切体调节免疫系统的机制。 肿瘤模型中转移前和转移微环境的动员、代谢变化和可塑性 病人。

Project Summary Cancer is a systemic disease. Its growth and malignant progression relies not only on the intrinsic aberrant genetic and epigenetic makeup of tumor cells, but also on the tumor-induced systemic factors which impact cells in local and distant microenvironments. Importantly, there is dynamic crosstalk between the tumor- educated tissues and organs and the tumor itself, especially during metastatic progression. As the tumor reshapes its local microenvironment, coaxing it to support cancer growth, it exerts systemic effects, conquering the immune system and distant organs, leading not only to metastasis but also to vascular changes (vascular leakiness, coagulation), muscular and metabolic changes (cachexia), liver and lung failure, changes in bone density (osteoporosis or osteopetrosis), and neuropathies, but maybe above all, inflammation and immune suppression. The tumor exerts its systemic effects, coaxing the various organ systems of the host to support cancer growth through tumor-secreted factors, such as soluble factors (cytokines and chemokines) and exosomes (and exomeres, the novel particles we recently discovered) nanovesicles that carry complex cargo, including proteins, metabolites, DNA and coding as well as non-coding RNAs. The development of effective anti-metastatic therapies is predicated on our understanding of these iterative and complex interactions between the tumor and its host, and on devising ways to interrupt this communication. We developed novel approaches to analyze the heterogeneity and functional roles of tumor-derived exosomes and exomeres in metastasis as well as their capacity to induce systemic changes. Ultimately, we propose to explore the possibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic cells could reverse immunosuppression, pre-metastatic niche formation and the systemic effects of cancer. In summary, we will focus on studying the mechanisms through which exosomes and exosomes regulate immune system mobilization, metabolic changes and plasticity of pre-metastatic and metastatic niches in cancer models and patients.