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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

基本信息

批准号：
10667590
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
项目类别：
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/10667590
关键词：
Address Adult Alleles Animals Apical Applications Grants 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 Heterozygote Homeostasis Knockout Mice Knowledge Laboratories Larva Lesion Lethal Genes Malignant - descriptor Malignant Neoplasms Mammalian Cell Microinjections Mitosis Mitotic spindle Modeling Molecular Mus Mutant Strains Mice Mutation NF-kappa B Normal tissue morphology Organism Orthologous Gene Pathway interactions Patients Phenotype Play Primary Cell Cultures Process Production Proliferating Proteins Regulation Role Signal Transduction Skin Sorting Squamous cell carcinoma 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 lentivirally transduced mammalian genome model organism mutant neoplastic novel programs self-renewal skin squamous cell carcinoma stem stem cell division stem cell niche stem cell self renewal stem cells stem-like cell targeted treatment tissue culture tumor

项目摘要

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.

正常组织的动态平衡是由成体干细胞和祖细胞维持的，这些干细胞和祖细胞使用细胞固有的机制和来自其微环境的信息来执行非常复杂的专门化类型有丝分裂称为不对称细胞分裂。这种分裂产生的两个子细胞获得了不同的细胞命运。当一个细胞继续增殖时，另一个子细胞从干细胞中撤出细胞利基，重塑其细胞间的相互作用，并启动一个程序，最终导致细胞循环撤退和分化。此过程可确保只有所需数量的单元格在任何给定的时间产生，每个组织中的细胞死亡和耗尽由出生的新的细胞。缺陷的不对称细胞分裂会导致正常组织动态平衡的失败和癌症干细胞的诞生，它不能产生能够正确地从细胞中撤出的后代循环和差异化。尽管细胞不对称分裂在组织动态平衡中起着关键作用，但几乎没有已知其在哺乳动物中的作用机制。对模型生物的研究揭示了关键细胞间相互作用和顶端-基底细胞极性在调节细胞不对称分裂中的作用。在果蝇中，基细胞极性基因致死巨型幼虫(LGL)被认为是一个重要的调节因子不对称细胞分裂和LGL突变导致分裂干细胞和癌症的发展。哺乳动物基因组包含两个LGL同源基因Llgl1和Llgl2。而上一次 LLGL1和LLGL2在癌细胞中的研究表明它们可能作为肿瘤抑制因子，这些基因在小鼠中的遗传分析因LIGL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、组织特异性的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抑瘤作用癌症。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内培养物慢病毒转导皮肤表皮以揭示LIGL基因家族的作用和分子机制在正常组织动态平衡和癌症期间的干细胞和祖细胞。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。