LEF/TCF Function in Adult Stem Cell Fate and Tumorigenesis

LEF/TCF 在成体干细胞命运和肿瘤发生中的功能

• 批准号: 7476553
• 负责人: STEPHEN R LYLE
• 金额: $ 27.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-08 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476553
• 关键词: Adult; Affect; Binding; Binding Sites; Biochemical; Cancer Biology; Cell Adhesion; Cell Line; Cell physiology; Cells; Characteristics; Code; Colon; Colon Carcinoma; Commit; Cutaneous; DNA Repair; DNA Sequence; Defect; Development; Dominant-Negative Mutation; Endometrial Carcinoma; Epithelial; Erinaceidae; Excision; Exons; Eye; Eyelid structure; Family; Frameshift Mutation; Gene Targeting; Genes; Genetic Transcription; Genomics; Genus Cola; Goals; Growth; Histopathologic Grade; Homeostasis; Human; Immunophenotyping; In Vitro; Incidence; Individual; Inherited; Lead; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Methods; Microsatellite Instability; Microsatellite Repeats; Mismatch Repair; Molecular; Morphology; Mus; Mutation; Mutation Analysis; Neoplasms; Nuclear; Oncogenic; Pathogenesis; Pathway interactions; Patients; Play; Property; Regulation; Relative (related person); Research Personnel; Risk; Role; Sampling; Sebaceous Adenocarcinoma; Sebaceous Gland Neoplasms; Signal Transduction; Skin; Skin Neoplasms; Stem cells; Surveys; Syndrome; System; TCF Transcription Factor; TCF7L2 gene; Techniques; Testing; Tissue Banks; Tissues; Transcriptional Activation; Transgenic Mice; Up-Regulation; Work; adult stem cell; carcinogenesis; cell growth; human stem cells; in vitro Assay; insight; malignant phenotype; neoplastic cell; novel; prevent; smoothened signaling pathway; stem cell fate; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to understand how specific genetic changes cause abnormal fate determination and growth regulation within adult epithelial stem cells and how these changes promote tumor formation from stem cells. The LEF/TCF family of transcription factors play an essential role in stem cell-mediated skin homeostasis. We have shown that human sebaceous tumors are similar to mouse tumors induced by a dominant negative Lef-1 gene and we recently identified mutations within the LEF-1 gene of sebaceous skin tumors. In addition, TCF-4 mutations occur in a significant proportion of colon cancers. Thus, our HYPOTHESIS is that LEF/TCF mutations cause abnormal stem cell fate determination and growth that promotes the formation of sebaceous tumors of the skin. Specific Aims: (1) Determine the cellular mechanisms by which dysregulated LEF-1 promotes tumorigenesis in multi-potent stem cells of human skin. (2) Determine the cellular and molecular properties of a new sebaceous tumor cell line showing deficient LEF-1 signaling. (3) Survey the spectrum and incidence of LEF/TCF mutations in human sebaceous skin tumors and correlate with tumor morphology. In order to accomplish these aims, we will use a novel system to isolate adult epithelial stem cells of human skin and study the cellular changes induced by altered LEF-1 signaling. We will use in vitro assays, as well as molecular and biochemical tests to characterize a new sebaceous tumor cell line. Lastly, a large archival tissue bank of sebaceous tumors will be screened by several molecular techniques to identify mutations within the LEF-1, TCF-3 and TCF-4 genes. Relevance: Patients with Muir-Torre syndrome, a genetically inherited defect of DNA repair, develop many sebaceous skin tumors and are at a high risk of colon cancer. Sebaceous tumors of the eyelid require removal of the eye in almost 25% of patients. This work should provide significant insights into the pathogenesis of sebaceous skin tumors, may lead to new ways of preventing or treating these tumors and may have broader implications for other cancers arising from adult epithelial stem cells.

描述(申请人提供)：这项提案的长期目标是了解特定的基因变化如何导致成人上皮干细胞内不正常的命运决定和生长调节，以及这些变化如何促进干细胞形成肿瘤。LEF/TCF转录因子家族在干细胞介导的皮肤动态平衡中起着重要作用。我们已经证明，人类皮脂腺肿瘤类似于由显性负向Lef-1基因诱导的小鼠肿瘤，最近我们发现皮脂腺肿瘤的Lef-1基因内存在突变。此外，TCF-4突变发生在相当大比例的结肠癌中。因此，我们的假设是，LEF/TCF突变导致异常的干细胞命运决定和生长，从而促进皮肤皮脂腺肿瘤的形成。具体目标：(1)确定失调的Lef-1促进人类皮肤多潜能干细胞肿瘤发生的细胞机制。(2)确定Lef-1信号缺失的新的皮脂腺肿瘤细胞系的细胞和分子特性。(3)检测皮脂腺肿瘤中Lef/Tcf基因突变的频率和发生率，并分析其与肿瘤形态的关系。为了实现这些目标，我们将使用一种新的系统来分离成人皮肤上皮干细胞，并研究Lef-1信号变化引起的细胞变化。我们将使用体外试验以及分子和生化试验来鉴定一种新的皮脂腺肿瘤细胞系。最后，将通过几种分子技术对皮脂腺肿瘤的大型档案组织库进行筛选，以确定Lef-1、TCF-3和TCF-4基因的突变。相关性：Muir-Torre综合征是一种遗传的DNA修复缺陷，患者会发展成许多皮脂腺皮肤肿瘤，并有患结肠癌的高风险。在几乎25%的患者中，眼睑皮脂腺肿瘤需要摘除眼睛。这项工作将为皮脂腺皮肤肿瘤的发病机制提供重要的见解，可能会导致预防或治疗这些肿瘤的新方法，并可能对成人上皮干细胞引发的其他癌症具有更广泛的影响。