Epi)Genomic drivers of primary and metastatic pancreatic islet cell carcinoma

Epi)原发性和转移性胰岛细胞癌的基因组驱动因素

• 批准号: 8637941
• 负责人: KENNETH W GROSS
• 金额: $ 17.01万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-18 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637941
• 关键词: Animal Model; Animals; Carcinogenesis Mechanism; Cell Differentiation process; Cells; Cessation of life; Clonal Evolution; Clonal Expansion; Clonality; Code; Collaborations; Color; CpG Islands; DNA Methylation; Development; Disease; Disease Progression; Dissection; Drug resistance; Endocrine Gland Neoplasms; Epigenetic Process; Etiology; Event; Exhibits; Exons; FDA approved; Fostering; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome; Genomics; Glucagon; Goals; Human; Hyperplasia; Individual; Investigation; Islet Cell; Islet Cell Tumor; Islets of Langerhans; Label; Letters; Literature; Liver; Location; Malignant neoplasm of pancreas; Metastatic Neoplasm to the Liver; Metastatic to; Methylation; Modeling; Molecular; Monitor; Mus; Mutation; Nature; Neoplasm Metastasis; Neoplasms; Neuroendocrine Tumors; Normal Cell; Pancreas; Pancreatic Endocrine Carcinoma; Pathology; Pathway interactions; Penetrance; Phenotype; Primary Neoplasm; Process; Protein Tyrosine Kinase; Recurrence; Renin; Renin-Angiotensin System; Reporter; Reporting; Resistance; Role; Route; SDZ RAD; Site; Stem cells; Symptoms; System; Therapeutic; TimeLine; Transcript; Work; carcinogenesis; cell type; clinically relevant; epigenome; epigenomics; exome; histogenesis; human disease; in vivo imaging; insulinoma; interest; islet; loss of function; lymph nodes; mTOR inhibition; metastatic process; methylome; mouse model; next generation sequencing; novel; public health relevance; response; transcriptomics; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Neuroendocrine tumors of the pancreas are relatively rare but there remains considerable interest in these entities because of the complexity of the tumor spectrum and the uncertain histogenesis. Unfortunately, animal models that can faithfully replicate human disease and enable a more thorough investigation of the etiology of the disease process are few. We have created what appears to be a remarkably useful new animal model for pancreatic islet cell carcinoma as a result of cell-specifically deleting floxed Rb and p53 loc within the renin- expressing cell compartment of pancreas. The predominant neoplasia observed is an islet cell carcinoma, expressing glucagon, which arises with high penetrance and exhibits symptoms and profound metastatic spread to sites representative of the human disease, resulting in death by 5-6 months. In the human disease the primary metastatic sites are regional lymph nodes and liver, which is mimicked by our model. This model exhibits unique features which will allow us to foster better understanding of pancreatic islet cell development, the role the renin-angiotensin system therein, islet cell carcinogenesis, and the associated metastatic process, with the aim of ultimately identifying genetic signatures for these processes. We hypothesize that renin is transiently expressed in early glucagon lineage differentiation and that the loss of p53 and Rb predisposes these islet cells to frank carcinogenesis upon the occurrence of stochastic co-operating genetic and epigenetic abnormalities. Furthermore, we propose that additional or specific genomic insults are required for the cells to acquire a metastatic phenotype. Our hypothesis is supported by our preliminary findings that the renin expressing cells co-localize with the alpha islet cells expressing glucagon and that both primary and metastatic tumors, stochastically arising, continue to express glucagon. This is further supported by recent literature demonstrating that human pancreatic progenitor cells exhibit highly regulated expression of various components of the renin-angiotensin system throughout the progenitor cell differentiation to various islet cell types. The current proposal will use Next Generation Sequencing of the exome, all transcripts, and of the methylome to identify co-operating mutations, gene expression changes and DNA methylation changes occurring within lineal descendants of the Rb-, p53-, renin-expressing cells of normal pancreatic islets that are associated with the stochastically arising primary tumors and corresponding liver metastases. Furthermore, the ability to use fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease pathology. We further expect that the Confetti reporter will assist in the identification o clonal expansion of individual colored cells in the islet for each primary tumor, and facilitate correctly pairing the colored metastatic tumor with the same colored primary tumor. This will increase the power of the pairwise comparisons between primary and metastatic tumors and will ultimately allow for dissection of multiple molecular routes of metastatic spread.

描述（由申请人提供）：胰腺神经内分泌肿瘤相对罕见，但由于肿瘤谱的复杂性和不确定的组织发生，对这些实体仍有相当大的兴趣。不幸的是，动物模型，可以忠实地复制人类疾病，使更彻底的调查病因的疾病过程是很少的。我们已经建立了一个非常有用的新的胰岛细胞癌动物模型，作为细胞特异性删除胰腺的肾素表达细胞区室内的floxed Rb和p53 loc的结果。观察到的主要瘤形成是表达胰高血糖素的胰岛细胞癌，其以高转移率出现，并表现出症状和向代表人类疾病的部位的严重转移性扩散，导致5-6个月死亡。在人类疾病中，主要转移部位是区域淋巴结和肝脏，这是我们的模型所模仿的。该模型具有独特的功能，这将使我们能够更好地了解胰岛细胞的发展，其中的作用，肾素-血管紧张素系统，胰岛细胞癌变，以及相关的转移过程，最终确定这些过程的遗传特征的目的。我们假设，肾素是短暂表达的早期胰高血糖素谱系分化和p53和Rb的损失，这些胰岛细胞坦率的癌变发生后，随机合作的遗传和表观遗传异常。此外，我们建议，额外的或特定的基因组损伤所需的细胞获得转移表型。我们的假设得到了我们初步发现的支持，即表达肾素的细胞与表达胰高血糖素的α胰岛细胞共定位，并且原发性和转移性肿瘤，偶然发生，继续表达胰高血糖素。最近的文献进一步支持了这一点，证明人胰腺祖细胞在整个祖细胞分化为各种胰岛细胞类型的过程中表现出高度调节的肾素-血管紧张素系统的各种组分的表达。当前提案将使用Next 对外显子组、所有转录物和甲基化组进行测序，以鉴定正常胰岛的Rb-、p53-、肾素表达细胞的直系后代中发生的协同突变、基因表达变化和DNA甲基化变化，这些变化与随机产生的原发性肿瘤和相应的肝转移有关。此外，使用荧光报告物用于贡献细胞的谱系追踪的能力也是有利的。 提供了一个独特的机会来剖析疾病病理学的时间轴。我们进一步预期，Confetti报告基因将有助于识别每个原发性肿瘤的胰岛中单个有色细胞的克隆扩增，并有助于正确配对有色转移性肿瘤与相同颜色的原发性肿瘤。这将增加原发性和转移性肿瘤之间的成对比较的能力，并最终允许解剖转移性扩散的多个分子途径。