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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：
10689255
负责人：
WEI GUO
金额：
$ 65.92万
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/10689255
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.

项目总结: