Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

分化平衡癌基因驱动的增殖以维持表皮稳态

基本信息

批准号：
10736269
负责人：
Slobodan Beronja
金额：
$ 60.09万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-27 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736269
关键词：
Adult Automobile Driving Behavior Biological Assay Biology Blood Vessels Cells Communication Cues DNA Damage Data Dermal Development Engineering Engraftment Ensure Environmental Hazards Ephrins Epidermis Epithelial Cells Epithelium Equilibrium Exposure to Failure Future Gene Targeting Genetic Epistasis Goals Growth Health Homeostasis Human Immunofluorescence Immunologic Life Ligands Maintenance Malignant Neoplasms Mediating Methods Molecular Mus Mutagens Mutate Mutation Neighborhoods Normal Cell Oncogenes Oncogenic Pathogenicity Pathologic Pathway interactions Pattern Phenotype Physically Challenged Population Proliferating Publishing Regulation Research Series Signal Pathway Signal Transduction Site Skin Stromal Cells Technology Testing Therapeutic Tissues Wild Type Mouse Work axon guidance cell type driver mutation epidermal stem cell frontier gain of function gene function improved innovation intercellular communication intravital imaging loss of function mouse model novel postmitotic prevent progenitor receptor response self-renewal stem cells synergism therapy design tumorigenesis two photon microscopy

项目摘要

Project Summary In skin epithelium, a population of progenitor cells distinctly capable of proliferation, self-renewal, and terminal differentiation into post-mitotic progeny, is responsible to sustain tissue homeostasis throughout life. In particular, the dynamic choice between renewal and differentiation has emerged as a critical regulator of the long-term fate of epidermal progenitors with cancer-driver oncogenic mutations, which are either rapidly eliminated through increased differentiation or tolerated as growth suppressed clones due to a stringent renewal/differentiation equilibrium. Our long-term objective is to establish how epidermal progenitor cells balance growth in the presence of oncogenic mutations to maintain tissue homeostasis. To do so, we will employ: (i) a mouse model that can initiate expression of oncogenic Hras in a single epidermal progenitor, (ii) intravital imaging to document growth from a single oncogenic cell to a stably integrated clone, (iii) a novel progenitor renewal assay to quantify dynamic cell fate choices accompanying clone expansion, and (iv) our recently developed methods to modify gene function in epidermal and stromal cells surrounding the oncogenic clone, to explore specific cellular and molecular mechanisms we hypothesize function are the interface of oncogenic cells and their microenvironment, and ensure skin homeostasis. This application aims to test the hypotheses that: 1.) Balanced progenitor renewal, critical to epidermal tolerance of oncogenic mutations, is coordinated across the tissue through short- and long-range non-cell autonomous interactions; 2.) Signaling between oncogenic clones and the surrounding normal epidermis, mediated by traditional axon guidance molecules, is required for balanced progenitor renewal and skin homeostasis; and 3.) Skin site-specific interaction between epidermal and stromal compartments can override oncogenic tolerance and lead to loss of tissue homeostasis. The results of our research are expected to immediately integrate our growing understanding of cell autonomous mechanisms of oncogenic tolerance into the broader, tissue-wide context critical to skin homeostasis. We expect these findings to inform future development of comprehensive strategies, focused on both the progenitor cell and its microenvironment, to manipulate its renewal potential and treat conditions marked by unrestrained epidermal growth.

项目摘要在皮肤上皮中，祖细胞的种群明显能够增殖，自我更新和末端分化为有丝分裂后的后代，负责在一生中维持组织稳态。尤其，更新和分化之间的动态选择已成为长期命运的关键调节者具有癌症驱动器致癌突变的表皮祖细胞，通过由于严格的更新/差异化，由于抑制克隆的抑制克隆而增加了分化或耐受性平衡。我们的长期目标是确定表皮祖细胞在存在下如何平衡生长致癌突变以维持组织稳态。为此，我们将采用：（i）可以启动的鼠标模型致癌性HRA在单个表皮祖细胞中的表达，（ii）插入式成像以记录从A的生长单一致癌细胞到稳定整合的克隆（iii）一种新型的祖细胞更新测定，以量化动态细胞克隆膨胀的命运选择，以及（iv）我们最近开发的修改基因功能的方法在致癌克隆周围的表皮和基质细胞中，探索特定的细胞和分子我们假设功能的机制是致癌细胞及其微环境的界面，以及确保皮肤稳态。该应用程序旨在测试以下假设：1。）平衡祖细胞更新，对表皮至关重要致癌突变的耐受性，通过短期和长期非细胞在整个组织中协调自主互动； 2.）致癌克隆和周围正常表皮之间的信号传导，由传统的轴突引导分子介导的平衡祖细胞和皮肤需要稳态； 3.）表皮和基质隔室之间的皮肤特定相互作用可以覆盖致癌性耐受性并导致组织稳态的丧失。预计我们的研究结果将立即整合我们对细胞的不断增长对皮肤至关重要的更广泛，整个组织的环境的致癌耐受性的自主机制稳态。我们希望这些发现将为未来的综合策略发展提供信息，重点是祖细胞及其微环境都可以操纵其更新潜力并处理标记的条件通过不受约束的表皮生长。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lentiviral in situ targeting of stem cells in unperturbed intestinal epithelium.

DOI：
10.1186/s12915-022-01466-1
发表时间：
2023-01-11
期刊：
BMC BIOLOGY
影响因子：
5.4
作者：
Garside, George B.;Sandoval, Madeline;Beronja, Slobodan;Rudolph, K. Lenhard
通讯作者：
Rudolph, K. Lenhard

Elimination of fluorescent protein immunogenicity permits modeling of metastasis in immune-competent settings.

DOI：
10.1016/j.ccell.2021.11.004
发表时间：
2022-01-10
期刊：
CANCER CELL
影响因子：
50.3
作者：
Grzelak, Candice A.;Goddard, Erica T.;Lederer, Emma E.;Rajaram, Kamya;Dai, Jinxiang;Shor, Ryann E.;Lim, Andrea R.;Kim, Jeanna;Beronja, Slobodan;Funnell, Alister P. W.;Ghajar, Cyrus M.
通讯作者：
Ghajar, Cyrus M.

Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth.