A physical sciences approach to investigate the role of exosomes in metastatic progression

研究外泌体在转移进展中的作用的物理科学方法

基本信息

批准号：
10737764
负责人：
WEI GUO
金额：
$ 11.55万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737764
关键词：
Address Adhesions Affect Aggressive behavior Biological Markers Biology Biomedical Engineering Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cancer Biology Cancer Patient Cell Culture Techniques Cells Cellular biology Cessation of life Clinical Clinical Pathology Collaborations Cytoskeleton Data Deposition Desmoplastic Development Devices Disease Disseminated Malignant Neoplasm Drug Kinetics Exhibits Extracellular Matrix Fostering Foundations Future Genetically Engineered Mouse Immune Evasion Immune checkpoint inhibitor Immune system Immunity Immunologic Surveillance Immunology Immunosuppression Immunotherapy In Vitro Invaded Isogenic transplantation Joints Link Macrophage Malignant Neoplasms Mechanics Mediating Membrane Metastatic/Recurrent Methods Modeling Modification Molecular Neoplasm Metastasis Non-Invasive Detection PD-1/PD-L1 Pathway interactions Patients Play Primary Neoplasm Process Production Publications Research Research Personnel Resistance Role Signal Transduction Site T-Lymphocyte Technology Testing Therapeutic Intervention Tissues Tumor Immunity Tumor Promotion Tumor Tissue Tumor-Derived United States Woman Xenograft Model Xenograft procedure anticancer research biophysical model cancer cell cell cortex cell growth clinically relevant exosome experimental study immunoregulation in vivo insight interest liquid biopsy mechanotransduction metastasis prevention mortality mouse model multi-scale modeling multidisciplinary neoplastic cell novel pharmacokinetic model physical science prevent protein transport response trafficking translational potential triple-negative invasive breast carcinoma tumor tumor immunology tumor microenvironment tumor progression

项目摘要

Project Summary: Metastatic cancer is a major clinical challenge that accounts for numerous deaths annually in the United States, particularly in women with triple-negative breast cancer (TNBC). Many tumors develop within a microenvironment (TME) characterized by altered/stiffened extracellular matrix (ECM) and compromised immunity. These alterations play a causal role in malignancy and metastasis. Recently tumor-derived exosomes have drawn tremendous interest as they are implicated in modulating the TME, suppressing anti-tumor immunity, and preparing the metastatic site for progression. A hallmark of cancer cells is their ability to evade the immune system. Exosomes play a pivotal role in the suppression of anti-tumor immunity. In this project, focusing on TNBC, we explore how ECM stiffness and cytoskeletal tension (collectively referred to as tissue tension) regulate exosome production and cargo composition, and how these exosomes contribute to the suppression of anti- tumor immunity and promote metastasis. We pursue a unique set of hypotheses linking tissue tension to exosome production and defining the role of tumor-derived exosomes in immune surveillance and metastatic progression. To test our hypotheses, we have assembled a strong team from UPENN and UCSF, integrating expertise in bioengineering, cancer mechanobiology, and cancer immunology. In Aim 1, we address whether and how the tissue tension affects exosome production and alters exosome cargo in vitro in TNBC cells. We will also delineate a molecular pathway linking ECM stiffness to intracellular signaling and exosome trafficking, using experimental and subcellular biophysical modeling methods. In Aim 2, we address how tissue tension promotes metastatic progression via exosomes in vivo. In this aim we test the hypothesis that the tension of the primary tumor tissue enhances exosome production and alters exosome cargo to promote the dissemination of primary tumor cells and foster their survival and outgrowth at the metastatic site. We will use unique genetically engineered mouse models (GEMMs) and syngeneic TNBC models, and TNBC patient PDXs, combined with multiscale pharmacokinetic modeling. In Aim 3, we address how tissue tension contributes to the suppression of anti-tumor immunity. In this aim, we will investigate the role of exosomes derived from tumors with high tension in stiff ECM TMEs in suppressing anti-tumor immunity through (1) reprogramming macrophages against T cells; and (2) the engagement of PD-1/PD-L1 checkpoint axis in T cells. We will use a combination of in vitro cell culture experiments, in vivo genetically engineered mouse models and syngeneic transplant manipulations and tissue-scale agent-based modeling. The expected results will shed light on the roles of exosomes in immune regulation and metastatic tumor progression; these are important and timely questions in cancer research. The results will lay the foundation for future therapeutic intervention of metastatic disease through the identification of actionable biomarkers, development of new immune checkpoint inhibitor (ICB)-based therapies, and ultimately reduce patient mortality.

项目概要：转移性癌症是一项重大的临床挑战，每年导致美国无数人死亡州，特别是患有三阴性乳腺癌（TNBC）的女性。许多肿瘤在体内形成微环境（TME）的特点是细胞外基质（ECM）改变/硬化和受损免疫。这些改变在恶性肿瘤和转移中发挥因果作用。最近肿瘤来源的外泌体引起了极大的兴趣，因为它们与调节 TME、抑制抗肿瘤免疫、并为转移部位的进展做好准备。癌细胞的一个标志是它们逃避免疫的能力系统。外泌体在抑制抗肿瘤免疫中发挥着关键作用。在这个项目中，重点关注 TNBC，我们探讨 ECM 硬度和细胞骨架张力（统称为组织张力）如何调节外泌体的产生和货物成分，以及这些外泌体如何有助于抑制抗- 肿瘤免疫并促进转移。我们追求一套独特的假设，将组织张力与外泌体的产生并定义肿瘤来源的外泌体在免疫监视和转移中的作用进展。为了检验我们的假设，我们组建了一支来自 UPENN 和 UCSF 的强大团队，将生物工程、癌症机械生物学和癌症免疫学方面的专业知识。在目标 1 中，我们解决是否以及组织张力如何影响 TNBC 细胞体外外泌体的产生并改变外泌体的货物。我们将还描绘了将 ECM 硬度与细胞内信号传导和外泌体运输联系起来的分子途径，使用实验和亚细胞生物物理建模方法。在目标 2 中，我们解决了组织张力如何促进通过体内外泌体的转移进展。为此，我们检验了以下假设：初级压力肿瘤组织增强外泌体的产生并改变外泌体货物以促进原发性肿瘤的传播肿瘤细胞并促进它们在转移部位的存活和生长。我们将利用独特的基因工程小鼠模型 (GEMM) 和同基因 TNBC 模型，以及 TNBC 患者 PDX，并结合多尺度药代动力学模型。在目标 3 中，我们讨论了组织张力如何有助于抑制抗肿瘤免疫力。为此，我们将研究源自高张力肿瘤的外泌体的作用在僵硬的 ECM TME 中，通过 (1) 针对 T 细胞重新编程巨噬细胞来抑制抗肿瘤免疫； (2) T 细胞中 PD-1/PD-L1 检查点轴的参与。我们将使用体外细胞的组合培养实验、体内基因工程小鼠模型和同基因移植操作以及组织规模基于代理的建模。预期结果将揭示外泌体在免疫中的作用调节和转移性肿瘤进展；这些是癌症研究中重要且及时的问题。这结果将为未来通过识别转移性疾病的治疗干预奠定基础可行的生物标记物，开发基于免疫检查点抑制剂（ICB）的新疗法，并最终降低患者死亡率。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantification of Curvature Sensing Behavior of Curvature-Inducing Proteins on Model Wavy Substrates.

DOI：
10.1007/s00232-022-00228-y
发表时间：
2022-06
期刊：
The Journal of membrane biology
影响因子：
0
作者：
通讯作者：

Data driven and biophysical insights into the regulation of trafficking vesicles by extracellular matrix stiffness.

DOI：
10.1016/j.isci.2022.104721
发表时间：
2022-08-19
期刊：
ISCIENCE
影响因子：
5.8
作者：
Parihar, Kshitiz;Nukpezah, Jonathan;Iwamoto, Daniel, V;Janmey, Paul A.;Radhakrishnan, Ravi
通讯作者：
Radhakrishnan, Ravi