ELUCIDATING MECHANISMS OF CELL COMPETITION DURING DEVELOPMENT

项目摘要 该提案的目标是了解细胞竞争如何调节组织生长， 以及这些机制如何在癌症等疾病中被颠覆。我们的实验室和其他实验室 已经表明，相邻种群之间的遗传异质性引发了竞争性的相互作用 他们之间，导致选择性消除较弱的人口（失败者）和扩大， 最强者（获胜者）。在经典的细胞竞争过程中，野生型细胞消除了活的但次优的细胞。 细胞这种类型的细胞竞争作为一种质量控制机制，以选择性地去除次优细胞。 组织中的细胞在超级竞争期间，具有较高水平的癌基因（如STAT和Myc）的细胞会杀死它们的细胞。 野生邻居超级竞争在癌症进展和转移中发挥作用。虽然竞争力 相互作用是保守的，越来越多的记录，机制调节消除 较弱的细胞或较强细胞的扩张知之甚少。通过下一代 通过测序，我们确定了STAT获胜者产生的两种可溶性应激反应因子， 提高他们的竞争力。在这里，我们将测试这些因素在细胞竞争中的作用。Aim 1聚焦 损伤反应途径在消除失败者或增加超级优胜赢家适应性中的作用， 竞争目的2将测试细胞外活性氧在杀死失败者和/或增强中的作用 经典细胞竞争和超级竞争中的赢家函数。我们设想我们的研究 阐明癌前细胞在组织内建立自身所采用的分子和细胞事件 当这些细胞发展成完全的肿瘤性病变时，这可能是有效的。

Project Summary The goal of this proposal is to understand how cell competition regulates tissue growth during development and how such mechanisms can be subverted during diseases like cancer. Our lab and other labs have shown that genetic heterogeneity between neighboring populations provokes competitive interactions between them, resulting in the selective elimination of the weaker population (the losers) and the expansion of the stronger one (the winners). During classical cell competition wild-type cells eliminate viable but sub-optimal cells. This type of cell competition functions as a quality control mechanism to selectively remove suboptimal cells from a tissue. During super-competition, cells with higher levels of oncogenes like STAT and Myc kill their wild-type neighbors. Super-competition functions during cancer progression and metastasis. While competitive interactions are conserved and are increasingly well documented, the mechanisms regulating the elimination of the weaker cells or the expansion of the stronger cells are poorly understood. Through next-generation sequencing, we identified two soluble stress-responsive factors that are produced by STAT winners and that promote their competitive fitness. Here, we will test the roles of these factors in cell competition. Aim 1 is focused on the role of the damage-response pathway in disadvantaging losers or increasing winner fitness in super- competition. Aim 2 will test the role of extracellular reactive oxygen species in killing losers and/or boosting winner function in both classical cell competition and super-competition. We envision that our studies will elucidate molecular and cellular events employed by pre-cancerous cells to establish themselves within a tissue and that might be operative when these cells progress into fully neoplastic lesions.