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：
9814413
负责人：
VALERI VASIOUKHIN
金额：
$ 39.56万
依托单位：
FRED HUTCHINSON CANCER RESEARCH 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/9814413
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 Stem cells Techniques Time Tissues Tumor Suppression Tumor Suppressor Proteins Withdrawal adult stem cell cancer initiation cancer stem cell daughter cell experimental study genetic analysis in utero in vivo interest mammalian genome mutant neoplastic novel progenitor programs self-renewal skin squamous cell carcinoma stem stem cell differentiation stem cell division stem cell niche 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.

正常组织的稳态由成体干细胞和祖细胞维持，它们利用细胞内在的来自微环境的机制和信息来执行非常复杂的专门类型有丝分裂称为不对称细胞分裂。该分裂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生态位，重塑其细胞间相互作用并启动一个程序，最终导致细胞循环退出和分化。这个过程确保只有必要数量的细胞在任何给定时间产生，并且每个组织中的细胞死亡和消耗通过产生来平衡新细胞。有缺陷的不对称细胞分裂可能导致正常组织稳态失败癌症干细胞的诞生，无法产生能够正常退出细胞的子细胞循环并微分。虽然不对称细胞分裂在组织稳态中发挥着关键作用，但很少有已知其在哺乳动物有机体中的机制。对模式生物的研究揭示了关键细胞间相互作用和顶基底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死巨幼虫（lgl）被确定为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的过度产生癌症的发展。哺乳动物基因组包含两个lgl直系同源物Llgl1和Llgl2。虽然之前对癌细胞系中 LLGL1 和 LLGL2 的研究表明它们作为肿瘤抑制因子的潜在作用，由于 Llgl 的遗传冗余和致死性，对小鼠中这些基因的遗传分析变得复杂突变体。我们现在已经产生了有条件的、组织特异性的 Llgl1/2 双敲除小鼠。我们的初步实验揭示Llgl1/2在皮肤鳞状细胞中的抑癌功能癌。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内皮肤表皮慢病毒转导揭示Llgl基因家族的作用和分子机制正常组织稳态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。