Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

项目摘要 在皮肤上皮中，一群祖细胞明显具有增殖、自我更新和终末分化的能力。 在有丝分裂后的后代中，细胞分化负责维持整个生命中的组织稳态。特别是， 更新和分化之间的动态选择已经成为长期命运的关键调节器 具有癌症驱动致癌突变的表皮祖细胞，这些突变要么通过 由于严格的更新/分化，增加的分化或耐受为生长抑制克隆 均衡 我们的长期目标是确定表皮祖细胞如何平衡生长， 致癌基因突变来维持组织内环境稳定。为了做到这一点，我们将采用：（i）可以启动 在单个表皮祖细胞中致癌Hras的表达，（ii）活体成像以记录从单个表皮祖细胞生长的过程， 单个致癌细胞到稳定整合克隆，（iii）定量动态细胞的新的祖细胞更新测定 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 在癌基因克隆周围的表皮和基质细胞中，探索特异性的细胞和分子生物学特性， 我们假设功能的机制是致癌细胞及其微环境的界面， 确保皮肤的稳态。 本申请旨在测试以下假设：1.）平衡的祖细胞更新，对表皮至关重要 致癌突变的耐受性，通过短距离和长距离的非细胞免疫在整个组织中协调。 自主互动; 2.）致癌克隆与周围正常表皮之间的信号传导， 由传统的轴突导向分子介导，是平衡祖细胞更新和皮肤所必需的。 稳态;和3.）表皮和基质间室的皮肤位点特异性相互作用可以覆盖 致癌耐受并导致组织稳态丧失。 我们的研究结果有望立即整合我们对细胞的不断增长的理解， 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 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，重点是 祖细胞及其微环境，以操纵其更新潜力并治疗标记为 是由表皮无限制的生长造成的

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.