Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue

正常胰腺组织中胰腺癌发生和发展的机制 在过去的30年里，许多癌症的存活率有所提高，但胰腺癌的存活率仍然很低。 由于缺乏早期检测方法和有效治疗，导管腺癌（PDAC）还没有。 转基因小鼠模型已被广泛用于研究PDAC发病机制。然而，老鼠 癌症模型可能会忽略人类和小鼠细胞之间的一些深刻差异。了解 人PDAC肿瘤发生的机制，我们建立了一个新的系统，分离和遗传 从正常人胰腺组织中操作原代腺泡细胞和导管细胞。这个独特的系统 为我们研究人类PDAC期间腺泡或导管细胞的最早变化提供了机会 入会仪式胰腺炎诱导的腺泡至导管化生（ADM）被认为是胰腺炎发生过程中最早的变化。 PDAC开发。使用我们的系统，我们在体外模拟腺泡到导管化生（ADM）， 单细胞水平，并确定TGFβ信号通路诱导人腺泡细胞中的ADM，部分 通过SMAD 4介导的途径。在ADM期间，细胞获得了新的特征性特性，包括短暂的 增殖能力然而，促进这些变化的潜在机制仍不清楚。我们将 使用我们的系统来进一步研究ADM过程。KRAS是最早和最频繁突变的 胰腺癌中的癌基因。然而，致癌KRAS启动肿瘤形成的机制不是 很好地理解，并且普遍接受的是，需要额外的遗传/表观遗传改变来 协同KRAS突变启动PDAC发展。我们发现突变的KRAS可以延长 AD细胞（已经经历ADM的腺泡细胞）的增殖。我们假设ADM相关的 这些变化与致癌的KRAS协同作用而引发胰腺癌。虽然SMAD 4通路是 由于ADM是必需的，该基因在晚期PDAC样本中经常突变，这表明它可能具有 在不同的细胞环境下有不同的功能。有趣的是，SMAD 4缺失的小鼠PDAC模型 发生导管内乳头状粘液性肿瘤（IPMN）而非胰腺上皮内瘤变 （PanIN）。这一结果是否是由于小鼠和人类之间的差异或由于不同的细胞 肿瘤的起源仍有待发现。建议的调查结果 研究将揭示PDAC肿瘤发生的人类特异性方面。这些研究的结果将 不仅提供了一个发现预后标志物的机会， 这可能导致癌症治疗新方法的发展。

Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue For the past thirty years, the survival rate for many cancers has improved, but survival for pancreatic ductal adenocarcinoma (PDAC) has not, due to lack of both early detection methods and effective treatments. Genetically modified mouse models have been widely used to study PDAC pathogenesis. However, mouse cancer models may overlook some profound differences between human and mouse cells. To understand the mechanisms of human PDAC tumorigenesis, we have established a novel system to isolate and genetically manipulate primary acinar cells and ductal cells from normal human pancreatic tissue. This unique system provides us with the opportunity to study the earliest changes in acinar or ductal cells during human PDAC initiation. Pancreatitis-induced acinar to ductal metaplasia (ADM) is considered to be the earliest change during PDAC development. Using our system, we recapitulated acinar to ductal metaplasia (ADM) in vitro at the single-cell level, and identified that the TGFβ signaling pathway induces ADM in human acinar cells, partially through SMAD4-mediated pathway. During ADM, cells gained new characteristic properties, including transient proliferative capacity. However, the underlying mechanisms facilitating these changes remain unclear. We will use our system to further investigate the ADM process. KRAS is the earliest and most frequently mutated oncogene in pancreatic cancer. However, the mechanism by which oncogenic KRAS initiates neoplasia is not well understood, and it is generally accepted that additional genetic/epigenetic alterations are required to cooperate with KRAS mutation to initiate PDAC development. We found that mutant KRAS can extend the proliferation of AD cells (acinar cells that have undergone ADM). We hypothesize that ADM-associated changes cooperate with oncogenic KRAS to initiate pancreatic cancer. Although the SMAD4 pathway is required for ADM, this gene is frequently mutated in the late-stage PDAC samples, suggesting that it may have distinct functions under different cellular contexts. Interestingly, mouse PDAC models with SMAD4 deletion developed intraductal papillary-mucinous neoplasm (IPMN) rather than pancreatic intraepithelial neoplasia (PanIN). Whether this result is due to differences between mice and humans or due to the different cell lineages from which the tumors developed remains to be discovered. The findings from the proposed investigations will reveal human-specific aspects of PDAC tumorigenesis. The outcomes of these studies will not only provide an opportunity to discover prognostic markers but also give us insight into PDAC tumorigenesis that may lead to development of new methods for cancer treatment.