权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Implantable pre-metastatic niche to elucidate the impact of chemotherapy-induced metastatic relapse

可植入的转移前生态位阐明化疗引起的转移复发的影响

基本信息

批准号：
10362620
负责人：
Jungwoo Lee
金额：
$ 35.18万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-11 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10362620
关键词：
3-Dimensional Adjuvant Adjuvant Therapy Algorithms Anti-Inflammatory Agents Biocompatible Materials Biomedical Engineering Blood Vessels Bone Marrow Cancer Biology Cancer Survivor Cell Count Cell physiology Cells Clinical Crystallization Data Development Dichloromethylene Diphosphonate Doxorubicin Endothelial Cells Engraftment Event Evolution Experimental Models FVB Mouse Female Goals Growth Hepatic Human Immune Immunocompetent Implant In Situ Individual Inflammation Inflammatory Interdisciplinary Study Liver Lobe Longitudinal Studies Measures Metastatic Neoplasm to the Liver Modeling Molecular Monitor Mouse Mammary Tumor Virus Mus Neoplasm Circulating Cells Neoplasm Metastasis Optics Organ Pharmaceutical Preparations Pharmacology Phase Phenotype Primary Neoplasm Prognosis Regimen Regulation Relapse Research Residual Tumors Resources Risk Secondary to Seeds Standardization Stromal Cells Techniques Therapeutic Time Tissue Engineering Tissue imaging Tissues Transgenic Organisms Transplantation Tumor Cell Biology Uncertainty United States Work anakinra anticancer research base biomedical imaging chemotherapy effectiveness evaluation epidemiologic data epidemiology study hydrogel scaffold imaging modality immunoregulation implant material improved intravital imaging macrophage metastasis prevention metastatic process mouse model neoplastic cell novel patient subsets porous hydrogel prevent quantitative imaging recruit scaffold standard of care subcutaneous therapeutic target tool tumor

项目摘要

Epidemiological studies indicate that chemotherapy can increase the chance of metastasis in a subset patients, but the underlying mechanism remains unclear because of a lack of relevant experimental models. The goal of this proposal is to elucidate the impact of chemotherapy on metastatic relapse with a tissue-engineered metastasis model that can capture metastatic niche evolution with a high level of molecular and cellular detail. Inspired by the recent discovery of the pre-metastatic niche (PMN) in major metastatic organs, we have developed a bone marrow stromal cell–seeded microfabricated porous hydrogel scaffold that creates a richly vascularized proinflammatory microenvironment when it is subdermally implanted in a mouse. This implantable PMN model has been shown to attract and support the engraftment and growth of circulating tumor cells and can be serially implanted in syngeneic naive mice for long-term studies. The semitransparent materials of the implant are compatible with quantitative imaging analysis via multiple imaging modalities including multiplex immunohistostaining, CLARITY-based optical sectioning of entire scaffolds, and intravital imaging via a skinfold window chamber. Our central hypothesis is that tissue inflammation and remodeling induced by chemotherapy activates dormant disseminated tumor cells and causes them to migrate and form in situ clusters as a function of cell number. Forming clusters could allow the cells to overcome microenvironmental regulation and regain an aggressive phenotype. We propose three specific aims: In Aim 1, we will generate subcutaneous and hepatic PMN models in a MMTV-PyMT female mouse and demonstrate the long-term evolution of metastatic niche by serially transplanting early metastatic niche established in primary mice to secondary syngeneic FVB mice. For this purpose, we will generate MMTV-Luc2-PyMT mice that allow non-invasive long-term bioluminescent monitoring of metastatic relapse. In Aim 2, we will use the techniques verified in Aim 1 to observe the effect of chemotherapy with doxorubicin on the metastatic process in serially implanted bone marrow and liver PMN models. In Aim 3, we will apply the established algorithm to measure potency to determine if adjuvant therapy with anti-inflammatory (anakinra) or anti-macrophage (clodronate) drugs reduces doxorubicin-induced metastatic relapse and will look at the effect of adjuvant timing. The proposed research is significant because it has the potential to facilitate the development of better therapeutic regimens that can eliminate active residual tumor cells without activating dormant disseminated tumor cells, and this would significantly improve long-term metastasis prevention.

流行病学研究表明，化疗可以增加一部分患者转移的机会，