DMS/NIGMS 2: Regulation of Cellular Stemness during the Epithelial-Mesenchymal Transition (EMT)

DMS/NIGMS 2：上皮-间质转化 (EMT) 期间细胞干性的调节

• 批准号: 2245957
• 负责人: Herbert Levine
• 金额: $ 120万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2245957&HistoricalAwards=false
• 关键词: DMS; NIGMS; Regulation; Cellular; Stemness

This research will involve a joint theoretical/experimental approach to address cell-fate trajectories that occur during induction of the epithelial-mesenchymal transition (EMT). The EMT transition was originally discovered in the context of developmental biology and refers to the fact that cells can dramatically change their phenotypic behavior from a sedentary, strongly-adherent lifestyle (“epithelial”) to one characterized by motility and weaker cell-cell coupling (“mesenchymal”). This transition was later shown to be directly relevant for the onset of metastatic spread of primary tumors. Recent efforts have indicated that epithelial cells can either undergo direct reprogramming to mesenchymal states or alternatively become more stem-like and exhibit intermediate, hybrid E/M properties. These latter states appear to be the most effective at initiating new tumors and hence the most dangerous. Based on the investigators’ preliminary investigations, state-of-the-art single cell measurement technology will be used together with advanced mathematical modeling frameworks to understand how cells choose specific fates and to quantitatively unravel the genetic and epigenetic dynamics that leads these cells along their particular trajectories. The investigators will develop new mathematical concepts such as the role of frustration in cell fate networks; here frustration refers to the incompatibility of various genetic interactions and understanding how it enables the aforementioned intermediate states can help develop ideas to interdict their effects. The investigators will also study the role of “epigenetic” modifiers, chemical modifications of proteins that help package the DNA that directly affect how easy it is to switch between different phenotypes. And, aside for the direct intellectual merit and possible spillovers into translational applications, this program will contribute the NSF’s “missing millions” goal by partnering with an HBCU to introduce this area of research to undergraduates from underrepresented groups.Technically, the projected research will consist of several interwoven areas coupling mathematics to biology. The investigators will take full advantage of modern single-cell technology to create datasets that will be used to quantitatively determine the step-by-step progress of EMT and concomitant stemness properties of cells, measuring both transcriptional profiles and features of the chromatin-dependent epigenetics. These data will help formulate new types of dynamical models, both deterministic and stochastic, coupling transcriptional regulation to a dynamically modifiable underling epigenetic landscape. These models will be used to understand the role of frustration, i.e. unsatisfied regulatory interactions in a given phenotypic state of the network, in the enabling of intermediate states with enhanced plasticity; this understanding could have direct translational relevance, as plasticity has been implicate in tumor initiation and in tumor therapy resistance. The data will also help develop and better understand the validity of advanced data analysis techniques such as the concept of optimal transport which allows for trajectory inference. This powerful idea requires the use of cost functions to relate data at different timepoints and the investigators will use both synthetic and actual data to explore the idea that incomplete mechanistic models can be used to create better such cost functions. All told, this research will greatly improve the understanding of cell-fate transitions and how they depend on the detailed molecular level underpinnings of genetic circuits governing transcriptional and translational processes and the epigenetic landscape to which these circuits are reciprocally coupled.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项研究将涉及一种联合理论/实验方法，以解决上皮 - 间质转变（EMT）期间发生的细胞污染轨迹。 EMT过渡最初是在发育生物学的背景下发现的，它指的是细胞可以将其表型行为从久坐的，强烈的生活方式（“上皮”）转变为运动性和以弱细胞细胞耦合为特征的事实。后来，这种过渡与原发性肿瘤转移扩散的发作直接相关。最近的努力表明，上皮细胞可以直接对间充质状态进行重新编程，或者变成更类似茎状和暴露的中间体杂交E/M特性。这些后来的状态似乎是启动新肿瘤的最有效的状态，因此最危险。基于研究者的初步研究，最先进的单细胞测量技术将与先进的数学建模框架一起使用，以了解细胞如何选择特定的命运并定量揭示导致这些细胞沿其特定轨迹的遗传和表观遗传动力学。研究人员将开发新的数学概念，例如挫败感在细胞脂肪网络中的作用；在这里，挫败感是指各种遗传相互作用的不相容性，并了解如何使优先考虑的中间状态可以帮助发展思想来阻止其影响。研究人员还将研究“表观遗传学”修饰剂的作用，即蛋白质的化学修饰，这些化学修饰有助于包装DNA直接影响不同表型之间切换的容易性。而且，除了直接的知识分子优点和可能溢出到翻译应用中，该计划还将通过与HBCU合作将这项研究领域介绍给本科生的本科生，从而为NSF的“缺失数百万”目标做出了贡献。预计，预计的研究将构成几个间周的研究领域，包括几个周期的研究领域。研究人员将充分利用现代单细胞技术的优势来创建数据集，以定量确定EMT和伴随的细胞的伴随干性特性的逐步进展，从而测量依赖染色质依赖性表观遗传学的转录谱和特征。这些数据将有助于制定新型的动态模型，包括确定性和随机模型，将转录调节耦合到动态修改的底层表观遗传景观。这些模型将用于理解挫败感的作用，即在给定表型状态下的不满意的调节性相互作用，以增强可塑性的中间状态。这种理解可能具有直接的转化相关性，因为可塑性已在肿瘤倡议和肿瘤疗法耐药性方面引起。数据还将有助于发展并更好地理解高级数据分析技术的有效性，例如最佳运输概念，该技术允许轨迹推理。这个有力的想法需要使用成本函数在不同的时间点上关联数据，并且研究人员将使用合成和实际数据来探讨不完整的机械模型可以使用来创建更好的成本功能的想法。总而言之，这项研究将极大地提高对细胞敏化过渡的理解，以及它们如何依赖于遗传回路的详细分子水平的基础，这些遗传回路的遗传回路和转录过程和翻译过程以及这些电路在互惠的依据中所依赖的表观遗传景观均表明了NSF的合法宣传和支持的良好依据，这些杂物是由NSF的众多范围进行了评估。 标准。

项目成果

Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP).

• DOI: 10.1016/j.tranon.2023.101837
• 发表时间: 2024-01
• 期刊: TRANSLATIONAL ONCOLOGY
• 影响因子: 5
• 作者: Catalanotto, Madison;Vaz, Joel Markus;Abshire, Camille;Youngblood, Reneau;Chu, Min;Levine, Herbert;Jolly, Mohit Kumar;Dragoi, Ana -Maria
• 通讯作者: Dragoi, Ana -Maria