Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

项目摘要 在皮肤上皮中，具有明显的增殖、自我更新和终末能力的一群祖细胞。 分化为有丝分裂后的后代，负责在一生中维持组织的动态平衡。特别是， 在更新和差异化之间的动态选择已经成为决定长期命运的关键因素 具有致癌基因突变的表皮祖细胞，这些突变要么通过 由于严格的更新/分化，导致分化增加或被容忍为生长抑制克隆 均衡。 我们的长期目标是建立表皮祖细胞如何在存在的情况下平衡生长 致癌基因突变以维持组织动态平衡。为此，我们将采用：(I)一种可以启动 致癌HRAs在单个表皮祖细胞中的表达，(Ii)活体成像研究 单个致癌细胞到稳定整合克隆，(Iii)一种新的用于定量动态细胞的祖细胞更新试验 伴随克隆扩张的命运选择，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 我们假设的作用机制是致癌细胞及其微环境的界面，以及 确保皮肤动态平衡。 本应用程序旨在验证以下假设：1.)平衡的祖细胞更新，对表皮至关重要 对致癌突变的耐受性，是通过短期和远程非细胞途径在整个组织中协调的 自主互动；2.)致癌克隆和周围正常表皮之间的信号， 由传统的轴突引导分子介导，是平衡祖细胞更新和皮肤所必需的 动态平衡；3.)表皮和基质隔间之间的皮肤部位特异性相互作用可以覆盖 致癌耐受性和导致组织动态平衡的丧失。 我们的研究结果有望立即整合我们对细胞日益增长的理解 致癌耐受的自主机制进入对皮肤至关重要的更广泛的组织范围 动态平衡。我们希望这些发现将为未来制定综合战略提供参考，重点是 祖细胞及其微环境，以操纵其更新潜力和治疗明显的疾病 通过不受限制的表皮生长。

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.