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: 10158454
• 负责人: VALERI VASIOUKHIN
• 金额: $ 34.02万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158454
• 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体干细胞和祖细胞维持， 机制和信息来执行非常复杂的专用类型 有丝分裂称为不对称细胞分裂。由此产生的两个子细胞获得 不同的细胞命运当一个细胞继续增殖时，另一个子细胞从干细胞中退出 细胞龛，重塑其细胞间的相互作用，并启动一个程序，最终导致细胞 周期退出和分化。这个过程确保了只有必要数量的细胞被 在任何给定的时间产生，每个组织中的细胞死亡和消耗都由 新的细胞有缺陷的不对称细胞分裂可导致正常组织稳态的失败， 癌症干细胞的诞生，它不能产生可以正确退出细胞的子细胞 循环和分化。虽然不对称细胞分裂在组织稳态中起着关键作用，但很少有 已知其在哺乳动物中的作用机制。对模式生物的研究表明， 细胞间相互作用和顶基细胞极性在调节细胞不对称分裂中的作用。 在果蝇中，基底细胞极性基因致死性巨幼虫（lgl）被确定为一个重要的调节因子 不对称的细胞分裂，lgl的突变导致分裂干细胞的过度产生， 癌症的发展。哺乳动物基因组含有两个lgl直系同源物Llgll和Llgl 2。虽然以前的 LLGL 1和LLGL 2在癌细胞系中的研究表明它们作为肿瘤抑制剂的潜在作用， 小鼠中这些基因的遗传分析由于Llgl的遗传冗余和致死性而变得复杂 变种人我们现在已经产生了条件性的、组织特异性的Llgl 1/2双敲除小鼠。我们 初步实验显示Llgl 1/2在皮肤鳞状细胞中具有抑瘤功能， carcinoma.在这项资助中，我们建议使用我们的突变动物，原代细胞培养和子宫内 慢病毒转导皮肤表皮揭示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干细胞和祖细胞中。这些研究将有助于 了解哺乳动物干细胞和祖细胞自我更新和分化的机制 以及这些机制在癌症中的作用。