Systemic regulation of metastasis

项目摘要 癌症是一种全身性疾病。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构成，也是对肿瘤诱发的全身性因素所产生的影响 在本地和远程微环境中的细胞。重要的是，在肿瘤之间存在动态串扰- 受教育的组织和器官以及肿瘤本身，特别是在转移进展期间。随着肿瘤 重塑其局部微环境，诱使它支持癌症生长，它发挥全身效应，征服 免疫系统和远处器官，不仅导致转移，而且导致血管变化（血管 渗漏、凝血）、肌肉和代谢变化（恶病质）、肝和肺衰竭、骨变化 密度（骨质疏松症或骨硬化症）和神经病变，但可能最重要的是，炎症和免疫 镇压肿瘤发挥其全身效应，诱使宿主的各种器官系统支持 通过肿瘤分泌的因子，如可溶性因子（细胞因子和趋化因子）和 外泌体（和外泌体，我们最近发现的新粒子）携带复杂货物的纳米囊泡， 包括蛋白质、代谢物、DNA和编码以及非编码RNA。制定有效 抗转移治疗是基于我们对这些反复和复杂的相互作用的理解 肿瘤和它的宿主之间的联系，以及设计中断这种联系的方法。我们开发了新的 分析肿瘤来源的外来体和外来体在肿瘤中的异质性和功能作用的方法 转移以及它们诱导全身变化的能力。最终，我们建议探索 抑制造血细胞中的特异性外泌体货物分子或其靶标可能 逆转免疫抑制、转移前小生境形成和癌症的全身效应。总的来说， 我们将重点研究外泌体和外泌体调节免疫系统的机制 癌症模型中转移前和转移小生境的动员、代谢变化和可塑性， 患者

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.