Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

项目概要 在皮肤上皮中，一群祖细胞明显能够增殖、自我更新和终末期 分化为有丝分裂后后代，负责维持整个生命过程中的组织稳态。特别是， 更新与分化之间的动态选择已成为长期命运的关键调节因素 具有癌症驱动致癌突变的表皮祖细胞，这些突变要么通过快速消除 由于严格的更新/分化，分化增加或耐受生长抑制克隆 平衡。 我们的长期目标是确定表皮祖细胞如何在存在以下因素的情况下平衡生长： 致癌突变以维持组织稳态。为此，我们将采用：（i）可以启动的小鼠模型 致癌 Hras 在单个表皮祖细胞中的表达，(ii) 活体成像以记录表皮祖细胞的生长情况 单个致癌细胞到稳定整合的克隆，（iii）一种新的祖细胞更新测定来量化动态细胞 伴随克隆扩增的命运选择，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与其微环境的界面，并且 确保皮肤稳态。 本应用旨在测试以下假设：1.) 平衡的祖细胞更新，对表皮至关重要 致癌突变的耐受性，通过短程和长程非细胞在组织内协调 自主交互； 2.) 致癌克隆与周围正常表皮之间的信号传导， 由传统轴突引导分子介导，是平衡祖细胞更新和皮肤所必需的 体内平衡； 3.) 表皮和基质室之间的皮肤部位特异性相互作用可以覆盖 致癌耐受性并导致组织稳态丧失。 我们的研究结果预计将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内 体内平衡。我们希望这些发现能够为未来制定综合战略提供信息，重点关注 祖细胞及其微环境，以操纵其更新潜力并治疗明显的病症 通过无限制的表皮生长。

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.