Temporally controlled oncogene expression in a novel pancreatic cancer model

新型胰腺癌模型中时间控制的癌基因表达

基本信息

批准号：
8337326
负责人：
Kay-Uwe Wagner
金额：
$ 16.15万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337326
关键词：
Ablation Accounting Address Adenocarcinoma Cell Adult Advanced Malignant Neoplasm Affect Apoptosis Appearance Biological Biological Models Cancer Cell Growth Cancer Model Cell Death Cell Survival Cell surface Cells Characteristics Data Detection Development Diagnosis Disease Down-Regulation Doxycycline Ductal Ductal Epithelial Cell Ductal Epithelium Epithelial Cells Event Exhibits Experimental Models Gene Expression Genes Genetic Goals Growth Human Label Laboratories Lesion Ligands Liver MYC gene Maintenance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Metastatic Carcinoma Metastatic Lesion Methods Molecular Carcinogenesis Molecular Target Mus Mutation Neoplasm Metastasis Neoplasms Neoplastic Cell Transformation Oncogenes Onset of illness Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Primary Lesion Recurrence Research Residual state Role Site Solid Staging Up-Regulation base c-myc Genes cancer cell cancer recurrence cancer stem cell in vivo Model interest mature animal mouse model neoplastic neoplastic cell novel pancreatic cancer cells pancreatic neoplasm progenitor response therapeutic target tumor tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): The long-term objective in our laboratory is to elucidate how genetic alterations contribute to malignant transformation of normal epithelial cells. Our current studies focus more closely on the continuous biological relevance of cancer initiating mutations during subsequent stages of malignant progression of pancreatic ductal adenocarcinoma (PDAC), which accounts for the majority of pancreatic malignancies. In addition, we aim to identify cellular subtypes that are primary targets for neoplastic transformation or for the maintenance of pancreatic cancers. Previous studies have demonstrated that not all genetic alternations that initiate neoplastic transformation are equally important for the survival of cancer cells. Consequently, the selection of appropriate molecular targets that are crucial for the growth of cancer cells is of the utmost importance. In preliminary studies, we found that the majority of human ductal precursor lesions (PanINs) highly express c-Myc, and this oncogene is also upregulated in a subset of primary and metastatic PDACs. To assess the role of c-Myc and other oncogenes during tumor initiation and progression, we have developed a novel mouse model that allows for a strong, ligand-controlled expression of genes in a temporally controlled manner in pancreatic ductal cells of adult animals. Using this unique mouse model, we can demonstrate that the upregulation of the c-Myc oncogene is sufficient to cause rapid transformation and the appearance of ductal neoplasia after a short latency period. These neoplastic lesions progress quickly into primary PDACs with sporadic metastases to the liver. The treatment of tumor-bearing mice with a ligand (doxycycline) results in the suppression of c-Myc expression, which subsequently leads to apoptosis of neoplastic cells within PanIN lesions and solid pancreatic tumors. The primary goal of the proposed studies is to further examine whether c-Myc is equally required for the survival of all or a subset of metastatic carcinoma cells. Based on our preliminary data, we hypothesize that ablating the expression of the c-Myc oncogene in invasive pancreatic adenocarcinoma cells will cause the regression of metastatic lesions in tumor-bearing mice. We anticipate that the vast majority of cancer cells will undergo cell death, but a few cells will remain dormant that might serve as precursors for disease recurrence. To experimentally address the hypothesis in an exploratory-type (R21) study, we will determine in the first specific aim the importance of the c-Myc oncogene during maintenance and metastatic progression of PDAC and how its significance in advanced cancers is affected by secondary genetic events. In the second aim, we will employ our unique cancer model to identify and characterize residual cells that survive the ablation of c- Myc expression, and we will assess whether these cells are responsible for disease recurrence. Collectively, the results of both specific aims will yield novel data about the importance of cancer-initiating genetic events during the final stages of PDAC progression as well the differential effects of the ablation of an oncogene on cancer cell subtypes that may facilitate disease recurrence.

描述（由申请人提供）：我们实验室中的长期目标是阐明遗传改变如何导致正常上皮细胞的恶性转化。我们目前的研究更加关注癌症导管腺癌（PDAC）随后癌症突变的连续生物学相关性，这是胰腺恶性肿瘤的大多数。此外，我们旨在鉴定细胞亚型，这是肿瘤转化或维持胰腺癌的主要靶标。先前的研究表明，并非所有引发肿瘤转化的遗传交替对于癌细胞的存活同样重要。因此，选择适当的分子靶标对于癌细胞的生长至关重要。在初步研究中，我们发现大多数人类导管前体病变（PANINS）高度表达C-Myc，并且这种癌基因在原发性和转移性PDAC的子集中也被上调。为了评估C-MYC和其他癌基因在肿瘤起步和进展过程中的作用，我们开发了一种新型的小鼠模型，该模型允许在成年动物的胰腺导管细胞中以时间控制的方式以颞基因的强烈，配体控制的表达。使用这种独特的小鼠模型，我们可以证明c-myc癌基因的上调足以引起快速转化和短期潜伏期后导管肿瘤的出现。这些肿瘤病变迅速发展为主要的PDAC，并向肝脏转移零星转移。用配体（强力霉素）治疗含有肿瘤的小鼠会导致C-MYC表达抑制，随后导致Panin病变和固体胰腺肿瘤内的肿瘤细胞凋亡。拟议研究的主要目标是进一步检查C-MYC是否同样需要全部或子集转移性癌细胞的存活。基于我们的初步数据，我们假设在浸润性胰腺腺癌细胞中消融c-myc癌基因的表达将导致肿瘤性小鼠转移性病变的消退。我们预计，绝大多数癌细胞将经历细胞死亡，但是一些细胞会处于休眠状态，这可能是疾病复发的前体。为了在探索性型（R21）研究中实验解决该假设，我们将在第一个特定的目标中确定C-Myc癌基因在PDAC的维持和转移进展过程中的重要性以及其在高级癌症中的重要性如何受次级遗传事件的影响。在第二个目标中，我们将采用我们独特的癌症模型来识别和表征在C- MYC表达消融的残留细胞，并评估这些细胞是否负责疾病复发。总体而言，这两个特定目标的结果将产生有关PDAC进展的最后阶段癌症遗传事件重要性的新数据，以及癌基因消融对癌细胞亚型的差异影响，这可能促进疾病复发。