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.

正常组织的稳态是由成体干细胞和祖细胞利用细胞内禀来维持的