Role of PD2/Paf1 in Pancreatic Acinar to Ductal Metaplasia

最近的证据提供了对分子机制和遗传变化的理解。 胰腺导管腺癌(PDAC)的潜在发病机制；然而，可用的信息有限 关于疾病的进展。对PDAC的几个基因工程小鼠模型的研究表明 腺泡细胞、中央腺泡细胞和/或假定的干细胞可负责 PDAC。这被认为是通过一种被称为“腺泡-导管化生”(ADM)的过程发生的，在这个过程中， 分化的细胞类型(腺泡)可逆地被另一种成熟的分化的细胞类型取代，这是一种条件 炎症时也可见，从而强调慢性胰腺炎患者易患上 PDAC。胰腺分化2(PD2)，也被称为聚合酶相关因子-1(Paf1)。 发现在PDAC中高表达，并显示出致癌潜力。我们之前的研究进一步 明确了PD2/Paf1在细胞周期调节和诱导PDAC染色质结构重塑中的作用 细胞。我们还证明了PD2/Paf1在小鼠多系分化中起着重要作用 胚胎干细胞和维持胰腺癌干细胞(PCSCs)。我们的初步努力是 研究PD2/Paf1在KrasG12D中的表达；Pdx1Cre小鼠模型显示，它是 在小鼠PDAC进展过程中肿瘤胰腺管中差异过表达的比较 在正常胰腺中有严格的腺泡表达。PD2/Paf1在`intermediate‘中专门表达 同时表达腺泡和导管特异性标志物的结构，代表着在 胰腺腺泡至导管化生。此外，我们还发现PD2/Paf1在PCSCs中过表达 小鼠组织和分离的CSCs中PDAC进展的标志物。这些CSCs的全能性质 使它们可以分化为几种类型的细胞。因此，这项研究的总体目标是确定角色 PD2/Paf1在PDAC进展中腺泡细胞向导管细胞的转分化中的作用，通过世系- 胰腺CSC群体分化的研究基于这些观察，我们的中心假设是 PD2/Paf1在腺泡到导管的化生过程中起着重要作用，从而促进了PDAC的发生。 进展，其过度表达有助于胰腺CSCs的导管谱系分化。至 验证这一假设，目标1将专注于研究腺泡到导管中PD2/Paf1的潜在联系 使用雨蛙素诱导的小鼠PDAC进展的化生模型。目标2将阐明这一机制(S) 使用腺泡细胞、器官3D培养和PD2-/-动物研究PD2/Paf1在腺泡到导管的化生中的作用。在AIM 3、了解PD2/Paf1在胰腺导管谱系分化中的作用机制 PDAC进展中的CSCs。综上所述，对PD2/Paf1在ADM进展中的新角色的理解 通过干细胞样细胞分化将为开发新的长期目标提供关键信息， 针对PDAC的靶向治疗。

Recent evidence has provided an understanding of the molecular mechanisms and genetic changes underlying pancreatic ductal adenocarcinoma (PDAC) pathogenesis; however, limited information is available on progression in the disease. Studies in several genetically engineered mouse models for PDAC suggest that acinar cells, centroacinar cells, and/or postulated stem cells can be responsible for the development of PDAC. This is believed to occur via a process termed “acinar-to-ductal metaplasia” (ADM), during which a differentiated cell type (acinar) is reversibly replaced with another mature, differentiated cell type, a condition also visible during inflammation, thereby underlining the predisposition of chronic pancreatitis patients to PDAC. Pancreatic differentiation 2 (PD2), also known as polymerase associated factor-1 (Paf1), has been found to be overexpressed in PDAC and to exhibit oncogenic potential. Our previous studies have further defined the role of PD2/Paf1 in cell cycle regulation and in inducing chromatin structure remodeling in PDAC cells. We have also demonstrated that PD2/Paf1 plays a major role in the multi-lineage differentiation of mouse embryonic stem cells and maintains pancreatic cancer stem cells (PCSCs). Our preliminary efforts to investigate the expression of PD2/Paf1 in KrasG12D;Pdx1Cre mouse model of PDAC showed that it is differentially overexpressed in neoplastic pancreatic ducts during murine PDAC progression, as compared to its strictly acinar expression in normal pancreas. PD2/Paf1 was specifically expressed in `intermediate structures' expressing both acinar and ductal specific markers, representing `transitional cells' during pancreatic acinar to ductal metaplasia. Further, we found that PD2/Paf1 is overexpressed along with PCSCs markers in PDAC progression in mouse tissues and isolated CSCs. The multi-potent property of these CSCs allows them to differentiate into several cell types. Therefore, the overall goal of this study is to define the role of PD2/Paf1 in trans-differentiation of acinar cells to ductal cells during PDAC progression, through lineage- differentiation of pancreatic CSC population. Based on these observations our central hypothesis is that “PD2/Paf1 plays a significant role in the process of acinar-to-ductal metaplasia, thereby contributing to PDAC progression, and its overexpression contributes to the ductal lineage-differentiation of pancreatic CSCs.” To test this hypothesis, Aim 1 will focus on investigating the potential link of PD2/Paf1 in acinar-to-ductal metaplasia using cerulein-induced mouse model of PDAC progression. Aim 2 will elucidate the mechanism(s) of PD2/Paf1 in acinar-to-ductal metaplasia using acinar cells, organoid 3D-cultures, and PD2-/- animals. In Aim 3, we will understand the functional mechanism of PD2/Paf1 in ductal lineage-differentiation of pancreatic CSCs in PDAC progression. Taken together, understanding of novel roles of PD2/Paf1 in ADM progression through stem-like cell differentiation will lead to critical information for the long-term goal of developing novel, targeted therapy against PDAC.