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：
10622445
负责人：
Jungwoo Lee
金额：
$ 34.4万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622445
关键词：
3-Dimensional Adjuvant Adjuvant Therapy Algorithms Anti-Inflammatory Agents Biocompatible Materials Biomedical Engineering Bone Marrow Cancer Biology Cancer Survivor Cell Count Cell physiology Cells Clinical Data Development Dichloromethylene Diphosphonate Doxorubicin Endothelial Cells Engraftment Event Evolution Experimental Models FVB Mouse Female Goals Growth Hepatic Human Immune Immune Evasion Immunocompetent Implant In Situ Individual Inflammation Inflammatory Interdisciplinary Study Liver Lobe Longitudinal Studies Macrophage Measures Metastatic Neoplasm to the Liver Modeling Molecular Monitor Mouse Mammary Tumor Virus Mus Neoplasm Circulating Cells Neoplasm Metastasis Optics Organ Pharmaceutical Preparations Phase Phenotype Primary Neoplasm Prognosis Regimen Regulation Relapse Research Residual Neoplasm Resources Risk Risk Reduction Secondary to Standardization Stromal Cells Techniques Therapeutic Time Tissue Engineering Tissue imaging Tissues Transgenic Organisms Transplantation Tumor Cell Biology Uncertainty United States Vascularization Work anakinra anticancer research biomedical imaging chemotherapy effectiveness evaluation epidemiologic data epidemiology study hydrogel scaffold imaging modality immunoregulation implant compatibility implant material improved intravital imaging metastasis prevention metastatic process migration mouse model neoplastic cell novel patient subsets pharmacologic polyoma middle tumor antigen 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部分患者转移的机会，但由于缺乏相关的实验模型，其潜在机制仍不清楚。该提案旨在通过组织工程手段阐明化疗对转移性复发的影响转移模型可以捕获具有高水平分子和细胞细节的转移生态位进化。受最近在主要转移器官中发现转移前生态位（PMN）的启发，我们开发了一种骨髓基质细胞接种的微制造多孔水凝胶支架，该支架创造了丰富的当将其皮下植入小鼠体内时，会产生血管化的促炎微环境。 PMN 模型已被证明可以吸引和支持循环肿瘤细胞的植入和生长，可以连续植入同系幼鼠体内进行长期研究。植入物与通过多种成像模式（包括多重成像）进行的成像分析兼容免疫组织染色、整个支架基于 CLARITY 的光学切片以及通过皮褶的活体成像窗室。我们的中心假设是化疗引起的组织炎症和重塑激活休眠的播散性肿瘤细胞，并导致它们作为细胞的功能迁移并形成原位簇形成簇可以使细胞克服微环境调节并恢复活力。我们提出了三个具体目标：在目标 1 中，我们将产生皮下和肝脏表型。在 MMTV-PyMT 雌性小鼠中建立 PMN 模型，并通过以下方法展示转移生态位的长期演变将原代小鼠中建立的早期转移生态位连续移植到继发同系 FVB 小鼠中。为此，我们将生成 MMTV-Luc2-PyMT 小鼠，允许非侵入性长期生物发光在目标 2 中，我们将使用目标 1 中验证的技术来观察转移复发的效果。阿霉素化疗对连续植入骨髓和肝脏PMN转移过程的影响在目标 3 中，我们将应用已建立的算法来测量效力以确定是否需要辅助治疗。与抗炎（阿那白滞素）或抗巨噬细胞（氯膦酸盐）药物一起使用可减少阿霉素诱导的转移性复发，并将研究辅助时机的效果。拟议的研究意义重大，因为它有潜力促进更好的治疗方案的开发，消除活性残留肿瘤细胞而不激活休眠的播散肿瘤细胞，这将显着改善长期预防转移。