Biology and Function of Exosomes in Cancer

外泌体在癌症中的生物学和功能

• 批准号: 10680453
• 负责人: RAGHU KALLURI
• 金额: $ 95.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680453
• 关键词: Address; Area; Biogenesis; Biology; Blood; Cell membrane; Cell secretion; Cells; Clinical; Complex; Diameter; Disease; Endosomes; Engineering; Genetic; Genomic DNA; Lipid Bilayers; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Messenger RNA; Methodology; MicroRNAs; Mus; Oncogenes; Organ; Pathogenesis; Pathology; Physiology; Production; Prognosis; Proteins; Research; Role; Source; Therapeutic Intervention; Tissues; Tropism; Tumor Immunity; United States; Untranslated RNA; cancer cell; design; engineered exosomes; exosome; extracellular; extracellular vesicles; in vivo; in vivo evaluation; intercellular communication; mouse model; nanosized; neoplastic cell; novel; novel diagnostics; novel therapeutics; programs; trafficking; translational applications; translational potential; treatment response; tumor microenvironment; tumor progression; tumor-immune system interactions

Abstract Trillions of exosomes, a subset of extracellular vesicles, are naturally present in the blood and tissue, and all cells secrete them into the extracellular milieu. Exosomes are on average around 100 nm in diameter and are speculated to have an endosomal origin, with a membrane lipid bilayer of similar orientation as the plasma membrane of the cells they originate from, and with capacity to enter other cells to deliver their constituents. The cargo exosomes include proteins, lipids, mRNA, non-coding RNAs (ncRNAs), microRNAs (miRNAs), and genomic DNA; and their production and content can vary depending on the cellular source. Exosomes may represent a novel mean of intercellular communication, but their biogenesis, trafficking, organ tropism, and impact on normal physiology and pathology in the in vivo setting is largely unknown. Similarly, the function of exosomes in pancreatic cancer remains understudied. Our research program is currently designed to address key unanswered scientific questions related to the basic biology of exosomes, their functional role in pathogenesis and therapeutic intervention of pancreatic cancer, a disease with dismal prognosis, and on the rise in the United States. Employing newly engineered mice, we propose to address the role of exosomes in the complex interplay between cancer cells, and the cells of the tumor microenvironment. Additionally, employing our established platform for clinical grade exosomes production, we will investigate the potential of engineered exosomes to target driver oncogenes and modulate the pancreatic cancer immune microenvironment/tumor immunity to facilitate therapeutic response. The proposed focus areas are rooted in the expertise we have developed within our research program over the last decade, and our track record provides the rationale and guidance for a higher chance of feasibility of the proposed studies, with potential for translational application.

摘要 数万亿个外泌体（细胞外囊泡的一个子集）天然存在于血液和组织中，所有 细胞将它们分泌到细胞外环境中。外泌体的平均直径约为100 nm， 推测具有内体起源，具有与血浆类似取向的膜脂质双层 它们起源于细胞的膜，并且具有进入其他细胞以递送其成分的能力。的 货物外泌体包括蛋白质、脂质、mRNA、非编码RNA（ncRNA）、微小RNA（miRNA）和 基因组DNA;并且它们的产生和含量可以根据细胞来源而变化。外泌体可以 代表了一种新的细胞间通讯方式，但它们的生物起源，运输，器官向性， 在体内环境中对正常生理和病理的影响在很大程度上是未知的。同样， 外泌体在胰腺癌中的作用还未得到充分研究。我们的研究计划目前旨在解决 与外泌体的基础生物学有关的关键未回答的科学问题，它们在 胰腺癌的发病机制和治疗干预，一种预后不良的疾病， 在美国利用新的工程小鼠，我们建议解决外泌体在肿瘤细胞中的作用。 癌细胞和肿瘤微环境细胞之间复杂的相互作用。此外，雇用 我们建立的临床级外泌体生产平台，我们将研究工程化的 外泌体靶向驱动癌基因并调节胰腺癌免疫微环境/肿瘤 免疫以促进治疗反应。建议的重点领域植根于我们拥有的专业知识 在过去十年中，我们的研究计划中开发了这些技术，我们的跟踪记录提供了理论依据， 为拟议研究的可行性提供更高机会的指导，并具有转化应用的潜力。

项目成果

Engineered exosomes targeting MYC reverse the proneural-mesenchymal transition and extend survival of glioblastoma.

• DOI: 10.1016/j.vesic.2022.100014
• 发表时间: 2022-12
• 期刊: Extracellular vesicle
• 作者: Amanda R. Haltom;Wafa E. Hassen;Janine Hensel;Jiha Kim;H. Sugimoto;Bingrui Li;Kathleen M. McAndrews;Meagan R. Conner;Michelle L. Kirtley;Xin Luo;Bingqing Xie;O. Volpert;Susan A. Olalekan;N. Maltsev;Anindita Basu;Valerie S. LeBleu;R. Kalluri