Regulatory Role of Mitochondrial DNA in Bladder Cancer Progression

线粒体 DNA 在膀胱癌进展中的调节作用

基本信息

批准号：
10575847
负责人：
JOHN A TAYLOR
金额：
$ 21.74万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10575847
关键词：
Advanced Malignant Neoplasm Affect Apoptosis Area Basic Science Biological Markers Biology Breast C3H/HeN Mouse Cancer Model Cancer cell line Cell Culture Techniques Cells Complement Credentialing DNA Data Development Diagnosis Disease Elements Event Exhibits Female Frequencies Future Genetic Genotype Goals Infiltration Inflammatory Inherited Intravenous Intrinsic factor Laboratories Malignant neoplasm of urinary bladder Measures Mediator Medical Metastatic Neoplasm to the Lung Mitochondria Mitochondrial DNA Modeling Mouse Strains Mus Neoplasm Metastasis Nitrosamines Nuclear Operative Surgical Procedures Outcome Pathogenicity Pathway interactions Patients Phenotype Predisposition Prevention Research Preventive Medicine Primary Neoplasm Prognostic Factor Proliferating Proteins Public Health Research Ribosomal RNA Role Sampling Signal Transduction Solid Neoplasm Target Populations Therapeutic Tissues Transfer RNA Transgenic Mice Tumorigenicity Variant Work advanced disease angiogenesis biomarker development cancer cell chemical carcinogen experience experimental study human disease improved laser capture microdissection lymph nodes malignant breast neoplasm melanoma mouse model neoplastic cell novel programs response transcriptome sequencing tumor tumor initiation tumor progression tumorigenesis

项目摘要

ABSTRACT Bladder cancer (BCa) is a common solid tumor and exhibits poor outcomes when regionally advanced or metastatic. Only modest improvements are seen even with aggressive surgical or medical treatments. Most patients with advanced cancer ultimately succumb to their disease with the most significant prognostic factor being the presence of metastasis. While much work has been done on identifying the presence of metastatic tumor cells in lymph nodes, little research currently explores the mechanisms that govern BCa progression to a metastatic phenotype. It is now well recognized that genetic factors, intrinsic to the primary tumor, and microenvironmental factors, independent of the primary tumor are involved in metastatic progression. One key understudied regulator of metastatic efficiency may be mitochondrial DNA (mtDNA). Variations in mitochondrial copy number and loss of mtDNA have been implicated as pathogenic events in BCa, and changes in mtDNA have been measured in patient samples; however, little is understood about the functional contribution of mtDNA to metastatic progression due to lack of suitable and available laboratory models. We have developed a model to determine contributions of mtDNA, designated MNX – mitochondrial-nuclear exchange. Transgenic mice are generated with matched nuclear DNA but different mtDNA from separate strains such that maternal inheritance determines mtDNA content in constant nuclear backgrounds. Prior studies from the Welch lab (mPI) using these mice in breast and melanoma models indicate mtDNA is a novel metastasis efficiency regulator. Moreover, mtDNA changes in the microenvironment independent of the tumor itself may further regulate the potential for metastasis. However, no such studies have been done in genetically credentialed models that accurately recapitulate human disease. Our preliminary data indicates that transfer of C3H/HeN mtDNA into a C57Bl/6J nuclear background results in more rapid tumor progression, especially in female mice. We hypothesize that specifically altering mitochondrial genetics will fundamentally alter tumor progression and metastasis rates in BCa via signaling changes in both tumor cells and the tumor stroma. We will use the highly credentialed N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced BCa model in murine strains with different rates of tumor formation (C3H/HeN and C57BL/6J) to investigate this hypothesis. In Specific Aim 1, we will evaluate the role of mtDNA in primary BCa tumor progression to metastasis using WT and MNX mice. In Specific Aim 2, we will determine the contribution of cellular and stromal elements to BCa metastasis in WT and MNX mice. These studies will define the role of mtDNA in this model and lead to future experiments understanding how loss or gain of mtDNA specifically effects both murine laboratory models and patients.

抽象的膀胱癌（BCA）是一种常见的实体瘤，当区域进展或转移。即使有侵略性的手术或医疗治疗，也只能看到适度的改进。最多晚期癌症患者最终屈服于最重要的预后因素是转移的存在。虽然已经为识别转移的存在做了很多工作淋巴结中的肿瘤细胞目前很少的研究探讨了控制BCA发展为A的机制转移表型。现在已经众所周知，遗传因素，原发性肿瘤的固有，微环境因子，与原发性肿瘤无关的转移性进展。一个钥匙转移性效率的调节剂可能是线粒体DNA（mtDNA）。线粒体的变化 MTDNA的拷贝数和丢失已暗示为BCA中的致病事件，MTDNA的变化已经在患者样本中测量；但是，关于mtDNA的功能贡献知之甚少由于缺乏合适和可用的实验室模型而导致转移性进展。我们已经开发了一个模型为了确定mtDNA的贡献，指定为MNX - 线粒体 - 核交换。转基因小鼠是用匹配的核DNA生成，但由不同的菌株产生不同的mtDNA 在恒定的核背景下确定mtDNA含量。 Welch Lab（MPI）的先前研究使用这些研究乳房和黑色素瘤模型中的小鼠表明mtDNA是一种新型的转移效率调节剂。而且，与肿瘤本身无关的微环境中的mtDNA变化可能会进一步调节潜力转移。但是，在遗传认证模型中尚未进行此类研究，这些模型准确地概括人类疾病。我们的初步数据表明，将C3H/HEN mtDNA转移到C57BL/6J 核背景会导致更快的肿瘤进展，尤其是在雌性小鼠中。我们假设这一点特异性改变线粒体遗传学将从根本上改变肿瘤进展和转移 BCA的率通过肿瘤细胞和肿瘤基质的信号变化。我们将使用高度认证的N-丁基N-（4-羟基丁基）硝基胺（BBN）诱导的BCA模型在不同的鼠菌株中肿瘤形成的速率（C3H/HEN和C57BL/6J）研究了这一假设。在特定目标1中，我们将使用WT和MNX小鼠评估mtDNA在原发性BCA肿瘤在转移中的作用。具体 AIM 2，我们将确定细胞和基质元素对WT和MNX中BCA转移的贡献老鼠。这些研究将定义mtDNA在该模型中的作用，并导致未来的实验理解 mtDNA的损失或增益如何特别影响鼠实验室模型和患者。