Multiscale functional mapping of cell identity decisions in PDAC initiation (P01)

胰腺癌进化的特点是通过分子重编程连续改变细胞命运。然而，我们对这些过程的理解是零散的。利用独特的人类细胞模型系统和新颖的小鼠筛选技术，该项目将绘制和功能化KRAS诱导的转录，表观遗传和拓扑变化，以创建驱动早期致癌细胞状态转变的分子程序的全局地图。综合分析将集中于核心转录因子网络的发现，随后是关键参与者的下游机制研究，如Foxp1，一个新发现的腺泡到导管化生的驱动因素。该项目对疾病的预防和治疗具有潜在的意义。

Pancreatic cancer evolution is characterized by consecutive cellular fate changes through molecular reprogramming. Our understanding of these processes is, however, fragmented. Utilizing unique human cellular model systems and novel screening technologies in mice, this project will chart and functionalize KRAS induced transcriptional, epigenetic and topological changes to create global maps of molecular programs driving early oncogenic cell state transitions. Integrative analyses will focus on the discovery of core transcription factor networks, followed downstream mechanistic studies on critical players, such as Foxp1, a newly identified driver of acinar to ductal metaplasia. The project has potential implications for disease prevention and therapy.