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Influence of hemodynamic shear stress on circulating tumor cells

血流动力学剪切应力对循环肿瘤细胞的影响

基本信息

批准号：
10442218
负责人：
Michael D Henry
金额：
$ 37.37万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442218
关键词：
Actomyosin Address Animal Model Behavior Biological Assay Biological Markers Biomechanics Blood Circulation Blood flow Cancer Biology Cancer Patient Cardiovascular system Cell Survival Cells Data Diagnostic Disease Drug Sensitization Epithelial Cells Event Exposure to Extravasation Genes Genetic Screening Genetic Transcription Goals Immune mediated destruction Intervention Knowledge Lead Liquid substance Literature Lung Malignant Neoplasms Measures Mechanics Mediating Metastatic to Microcirculation Mission Molecular Neoplasm Circulating Cells Neoplasm Metastasis Outcome Pharmaceutical Preparations Plasma Predisposition Primary Neoplasm Publishing Research Resistance Role Solid Neoplasm Testing Therapeutic Tissues Traction Tumor Cell Biology base cancer cell cancer diagnosis cancer therapy cancer type clinically actionable effectiveness evaluation experience genetic analysis hemodynamics improved in vivo innovation insight knock-down mechanical force metastatic process mouse model novel novel diagnostics novel therapeutic intervention novel therapeutics prevent programs response shear stress tumor microenvironment

项目摘要

Circulating tumor cells (CTCs) are exposed to various insults thought to reduce their survival including lack of anchorage and trophic support from the primary tumor microenvironment, immune-mediated destruction and exposure to hemodynamic forces that may mechanically destroy them. However, the relative contribution of these factors to CTC survival and their overall role in metastasis is unclear. It has recently been shown that cancer cells from many tissue origins actively resist destruction by fluid shear stress (FSS), implying that viable CTCs are not mechanically fragile as suspected. Our long-term goal is to understand the biomechanical influences on CTCs and how this contributes to metastasis. The objective of this proposal is to determine the mechanism of FSS resistance in cancer cells and its role in metastatic colonization. Our central hypothesis is that mechano-adaptation of viable CTCs to FSS promotes their survival in the circulation and “primes” them for subsequent events in metastasis. Our hypothesis is based on our previously published and preliminary data presented below as well as recently published data from others which is supportive of our hypothesis. The rationale for the proposed research is that once we understand the mechanism underlying FSS resistance; this would represent a novel therapeutic approach aimed at decreasing the survival of CTCs by enhancing their destruction due to the mechanical forces that naturally exist in the circulation. Guided by preliminary data, the central hypothesis will be tested by pursuing the following specific aims: 1) Define molecular mechanisms of FSS resistance; 2) Determine the effect of FSS exposure on metastatic colonization; 3) Determine the effectiveness of inhibiting FSS resistance as an anti-metastatic strategy. To accomplish these aims, we will employ a forward genetic screen to identify novel genes that mediate FSS resistance and determine their involvement with RhoA- actomyosin interactions. Short-term survival of CTCs will be assessed using a novel mouse model to measure entrapment of intact CTCs in the lung and destruction of CTCs measured by a plasma biomarker. We will validate novel genes identified in a forward genetic screen in similar assays. We will determine the involvement of RhoA- YAP activation by FSS in supporting the survival and extravasation of cancer cells lodged in the microcirculation. Finally, we will test the potential of clinically actionable drugs that sensitize cells to FSS as well as conditional RhoA/YAP knockdown to block productive metastatic colonization in mouse models. The proposed research is innovative because, it represents a paradigm shift from the idea that CTCs are mechanically fragile by elucidating a mechanism whereby viable CTCs actively resist destruction by hemodynamic forces and drives further events in metastasis. The proposed research is significant because defining the mechanisms and consequences of FSS resistance in CTCs will open entirely new diagnostic and therapeutic possibilities in cancer patients.

循环肿瘤细胞（ctc）暴露于各种被认为会降低其生存的损伤，包括缺乏