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

• 批准号: 10273891
• 负责人: WEI GUO
• 金额: $ 68.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10273891
• 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; 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; Isogenic transplantation; Joints; Light; Link; Malignant Neoplasms; Mechanics; Mediating; Membrane; Methods; Modeling; Modification; Molecular; Neoplasm Metastasis; Non-Invasive Cancer Detection; PD-1/PD-L1; Pathway interactions; Patients; Play; Primary Neoplasm; Process; Production; Publications; Recurrence; Research; Research Personnel; Resistance; Role; Signal Transduction; Site; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Time; Tissues; Tumor Immunity; Tumor Tissue; Tumor-Derived; United States; Woman; Xenograft Model; Xenograft procedure; anticancer research; base; biomarker development; biophysical model; cancer cell; cell growth; clinically relevant; exosome; experimental study; immunoregulation; in vivo; insight; interest; liquid biopsy; macrophage; mechanotransduction; metastasis prevention; mortality; mouse model; multi-scale modeling; multidisciplinary; neoplastic cell; novel; pharmacokinetic model; physical science; prevent; protein transport; response; trafficking; triple-negative invasive breast carcinoma; tumor; tumor immunology; tumor microenvironment; tumor progression

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.

项目总结： 在美国，转移性癌症是一项重大的临床挑战，每年导致无数人死亡。 在各州，特别是在患有三阴性乳腺癌(TNBC)的妇女中。许多肿瘤在 以细胞外基质(ECM)改变/硬化和受损为特征的微环境(TME) 豁免权。这些改变在恶性肿瘤和转移中起着因果作用。最近肿瘤来源的外切体 引起了极大的兴趣，因为它们涉及调节TME，抑制抗肿瘤免疫， 并为进展的转移部位做准备。癌细胞的一个特点是它们能够逃避免疫。 系统。外切体在抑制抗肿瘤免疫中起着关键作用。在这个项目中，重点是 ，我们探索细胞外基质硬度和细胞骨架张力(统称为组织张力)是如何调节的。 外切体的生产和货物组成，以及这些外切体如何有助于抑制抗- 促进肿瘤免疫和转移。我们追求一组独特的假说，将组织张力与 外切体的产生和确定肿瘤来源的外切体在免疫监测和转移中的作用 进步。为了验证我们的假设，我们从宾夕法尼亚大学和加州大学旧金山分校组建了一个强大的团队，整合了 在生物工程、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，我们讨论是否 以及组织张力如何影响体外培养的TNBC细胞中外切体的产生和改变外切体的运输。我们会 还描绘了一条将细胞外基质刚性与细胞内信号和外切体运输联系起来的分子途径，使用 实验和亚细胞生物物理模拟方法。在目标2中，我们解决了组织张力如何促进 体内通过外切体的转移进展。在这个目的中，我们检验了这样的假设，即初级粒子的张力 肿瘤组织增强外切体的产生和改变外切体的运输促进原发肿瘤的扩散 并促进肿瘤细胞在转移部位的存活和生长。我们将使用独特的基因 工程小鼠模型(GEMM)和同基因TNBC模型，以及TNBC患者PDX，与 多尺度药代动力学模型。在目标3中，我们解决了组织张力如何有助于抑制 抗肿瘤免疫。在这个目标中，我们将研究来自肿瘤的外切体在高张力下的作用。 在僵硬的ECM中，TME通过(1)巨噬细胞对T细胞的重新编程来抑制抗肿瘤免疫； (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 基于组织规模代理的建模。预期的结果将阐明外切体在免疫中的作用。 调控与肿瘤转移进展；这些都是癌症研究中重要而及时的问题。这个 研究结果将为今后转移性疾病的治疗干预奠定基础。 可操作生物标记物的开发，基于免疫检查点抑制物(ICB)的新疗法的开发，并最终 降低患者死亡率。