Basal Cell Polarity Proteins in Normal Tissue Homeostasis and Cancer

正常组织稳态和癌症中的基底细胞极性蛋白

• 批准号: 10406262
• 负责人: VALERI VASIOUKHIN
• 金额: $ 39.45万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406262
• 关键词: Address; Alleles; Animal Model; Animals; Apical; Basal Cell; Biochemical; Biological Assay; Birth; Bromodeoxyuridine; Cancer cell line; Cell Cycle; Cell Death; Cell Differentiation process; Cell Polarity; Cell Separation; Cell division; Cells; Characteristics; Chromosomes; Complex; Data; Daughter; Development; Drosophila genus; Ensure; Epidermis; Event; Failure; Future; Gene Family; Gene Targeting; Genes; Genetic; Genetic Crossing Over; Grant; Homeostasis; Knockout Mice; Knowledge; Laboratories; Larva; Lesion; Lethal Genes; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Microinjections; Mitosis; Mitotic spindle; Molecular; Mus; Mutant Strains Mice; Mutation; NF-kappa B; Normal tissue morphology; Organism; Orthologous Gene; Pathway interactions; Patients; Phenotype; Play; Primary Cell Cultures; Process; Proteins; Regulation; Role; Signal Transduction; Skin; Sorting - Cell Movement; Squamous cell carcinoma; Stem Cell Development; Techniques; Time; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Withdrawal; adult stem cell; cancer initiation; cancer stem cell; daughter cell; epidermal stem cell; experimental study; genetic analysis; in utero; in vivo; interest; mammalian genome; mutant; neoplastic; novel; programs; self-renewal; skin squamous cell carcinoma; stem; stem cell differentiation; stem cell division; stem cell niche; stem cell self renewal; stem cells; stem-like cell; targeted treatment; tissue culture; tumor

Normal tissue homeostasis is maintained by adult stem and progenitor cells that use cell intrinsic mechanisms and information from their microenvironment to execute a very complex specialized type of mitosis known as asymmetric cell division. Two resulting from this division daughter cells acquire different cell fates. While one cell continues proliferation, another daughter cell withdraws from the stem cell niche, remodels its intercellular interactions and starts a program which ultimately leads to the cell cycle withdrawal and differentiation. This process ensures that only the necessary number of cells is produced at any given time and the cell death and depletion in each tissue is balanced by the birth of new cells. Defective asymmetric cell division can result in the failure of normal tissue homeostasis and birth of cancer stem cells, which cannot produce daughters that can properly withdraw from the cell cycle and differentiate. While asymmetric cell division plays a pivotal role in tissue homeostasis, little is known about its mechanisms in mammalian organisms. Studies in model organisms revealed critical role of intercellular interactions and apical-basal cell polarity in regulation of asymmetric cell division. In Drosophila, basal cell polarity gene lethal giant larvae (lgl) was identified as an important regulator of asymmetric cell division, and mutations in lgl result in overproduction of dividing stem cells and development of cancer. Mammalian genomes contain two lgl orthologs Llgl1 and Llgl2. While previous studies of LLGL1 and LLGL2 in cancer cell lines indicated their potential role as tumor suppressors, genetic analysis of these genes in mice was complicated by the genetic redundancy and lethality of Llgl mutants. We have now generated conditional, tissue specific Llgl1/2 double knockout mice. Our preliminary experiments revealed tumor-suppressive function of Llgl1/2 in skin squamous cell carcinoma. In this grant, we propose to use our mutant animals, primary cell cultures and in utero lentiviral transduction of skin epidermis to reveal the role and molecular mechanisms of Llgl gene family in stem and progenitor cells during normal tissue homeostasis and cancer. These studies will help to understand the mechanisms of mammalian stem and progenitor cells self-renewal and differentiation and the role of these mechanisms in cancer.

正常的组织稳态由成人茎和祖细胞维持，这些细胞使用细胞固有 来自其微环境的机制和信息，以执行非常复杂的专业类型 有丝分裂称为不对称细胞分裂。该分区子细胞产生的两个 不同的细胞命运。一个细胞继续扩散，另一个女儿细胞从茎上退出 细胞小众，重塑其细胞间相互作用并启动一个程序，该程序最终导致细胞 循环提取和分化。此过程可确保只有必要数量的单元格是 在任何给定时间产生，每个组织中的细胞死亡和耗竭都可以通过 新细胞。有缺陷的不对称细胞分裂会导致正常组织稳态失败，并且 癌症干细胞的诞生，无法产生可以正确退出细胞的女儿 周期和区分。而非对称细胞分裂在组织稳态中起关键作用，但很少 关于其在哺乳动物生物中的机制已知。模型生物的研究揭示了关键 细胞间相互作用和顶端基细胞极性在不对称细胞分裂调节中的作用。 在果蝇中，基底细胞极性基因致命巨型幼虫（LGL）被确定为重要调节剂 非对称细胞分裂和LGL突变导致分裂干细胞和 癌症的发展。哺乳动物基因组含有两个LGL直系同源物LLGL1和LLGL2。以前 癌细胞系中LLGL1和LLGL2的研究表明它们作为肿瘤抑制剂的潜在作用， LLGL的遗传冗余性和致死性使这些基因的遗传分析变得复杂 突变体。现在，我们已经产生了有条件的组织特异性LLGL1/2双基因敲除小鼠。我们的 初步实验揭示了LLGL1/2在皮肤鳞状细胞中的肿瘤抑制功能 癌。在这笔赠款中，我们建议使用我们的突变动物，原代细胞培养物和子宫 皮肤表皮的慢病毒转导，以揭示LLGL基因家族的作用和分子机制 在正常组织稳态和癌症期间的茎和祖细胞中。这些研究将有助于 了解哺乳动物茎和祖细胞的机制自我更新和分化 这些机制在癌症中的作用。