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，化学疗法可以增加子群患者转移的机会，但是，由于缺乏相关的实验模型，基本机制仍然不清楚。目标该建议是阐明化学疗法对通过组织工程的转移缓解的影响转移模型可以捕获具有高水平的分子和细胞细节的转移性利基进化。受到最近在主要转移器官中发现的中转移利基（PMN）的启发，我们有开发了一个基质细胞的骨髓 - 种子的微生物水凝胶A支架，可产生丰富的血管促炎微环境将其下植入小鼠时。这个植入已显示PMN模型吸引和支持循环肿瘤细胞的植入和生长可以在合成的天真小鼠中串行植入长期研究。半透明的材料植入物通过多种成像方式（包括多路复用）与定量成像分析兼容免疫疗法，基于清晰的整个支架的光学切片，以及通过皮肤折叠的浸润成像窗室。我们的中心假设是，化学疗法诱导的组织炎症和重塑会激活休眠的散布肿瘤细胞，并导致它们随着细胞的函数而迁移并形成原位簇数字。形成簇可以使细胞克服微环境调节并持续存在积极的表型。我们提出了三个具体目标：在AIM 1中，我们将产生皮下和肝 MMTV-PYMT雌鼠中的PMN模型，并证明了转移性生态位的长期演变在初级小鼠中建立的辅助转移性壁裂的序列移植到继发性FVB小鼠中。为了此目的，我们将生成MMTV-LUC2-PYMT小鼠，允许非侵入性长期生物发光监测转移性缓解。在AIM 2中，我们将使用AIM 1中验证的技术来观察阿霉素的化学疗法在连续植入的骨髓和肝PMN的转移过程中型号。在AIM 3中，我们将应用已建立的算法来测量效力以确定是否辅助治疗抗炎（Anakinra）或抗巨噬细胞（Clodronate）药物减少了阿霉素诱导的转移性缓解，并将研究辅助时机的效果。拟议的研究很重要，因为它有可能促进更好的治疗方案的发展，以消除主动残留肿瘤细胞而不激活休眠的肿瘤细胞，这将显着改善长期预防转移。