An epigenetic switch controlling pancreatic cancer susceptibility

描述（由申请方提供）：尽管KRAS癌基因的激活突变普遍存在于胰腺导管腺癌（PDAC）及其最早的前驱病变胰腺上皮内瘤变（PanIN）中，但动物模型研究表明，仅该突变不足以启动转化。相反，额外的刺激与RAS协同作用以促进转化，并且这种协同作用首先在PDAC产生的外分泌腺泡细胞的导管重编程中明显。我们假设，维持腺泡分化的表观遗传程序构成了这些细胞中的一种新的肿瘤抑制机制，并且腺泡分化调节因子与RAS信号通路的相互抑制相互作用在正常和转化细胞表型之间产生了一个快速开关。特别地，我们提出，转录因子Ptf 1a（腺泡分化的主调节因子）的正性自身调节在PDAC起始期间被靶向抑制，并且其活性的恢复可以使转化的细胞恢复到静止和分化状态。我们将在小鼠PDAC模型中检验这一假设，该模型基于成人腺泡细胞中致癌KrasG 12 D的Cre依赖性表达，在那里我们发现Ptf 1a基因的缺失极大地促进了转化。我们在这项初步研究中提出了两个具体的目标，结合假设驱动和发现为重点的方法：（1）确定Ptf 1a下调是否是成人腺泡细胞RAS转化的必要和充分条件;（2）确定Ptf 1a功能和RAS信号交叉抑制相互作用的潜在表观遗传机制。这些实验利用了PI和co-PI在小鼠PDAC模型和腺泡基因调控方面的专业知识，并提出了一种新的和潜在的靶向机制，用于这种目前难治性疾病的肿瘤起始。

DESCRIPTION (provided by applicant): Although activating mutations of the KRAS oncogene are ubiquitous in pancreatic ductal adenocarcinoma (PDAC) and its earliest precursor lesions, pancreatic intraepithelial neoplasia (PanIN), animal model studies indicate that this mutation alone is not sufficient to initiate transformation. Instead, additional stimuli synergize with RAS o promote transformation, and this synergy is first evident in ductal reprogramming of the exocrine acinar cells from which PDAC arises. We hypothesize that the epigenetic program sustaining acinar differentiation constitutes as a novel tumor suppressive mechanism in these cells, and that mutual inhibitory interactions of acinar differentiation regulators with the RAS signaling pathway create a bistable switch between normal and transformed cell phenotypes. In particular, we propose that positive autoregulation of the transcription factor Ptf1a, a master regulator of acinar differentiation, is targeted for inhibition during PDAC initiation, and that restoration of its activity could restore transformed cells to a quiescent and differentiated state We will test this hypothesis in a mouse PDAC model, based on Cre- dependent expression of oncogenic KrasG12D in adult acinar cells, where we have discovered that genetic loss of Ptf1a dramatically enhances transformation. We propose two specific aims in this pilot study, combining hypothesis-driven and discovery-focused approaches: (1) determine whether Ptf1a downregulation is necessary and sufficient for RAS transformation of adult acinar cells; (2) identify potential epigenetic mechanisms for cross-inhibitory interactions of Ptf1a function and RAS signaling. These experiments take advantage of the PI and co-PI's expertise in mouse PDAC models and acinar gene regulation, and address a novel and potentially targetable mechanism for tumor initiation in this currently intractable disease.