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

人正常胰腺组织中胰腺癌发生发展机制的研究 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 由于缺乏早期发现方法和有效的治疗方法，导管腺癌(PDAC)尚未得到有效的治疗。 转基因小鼠模型已被广泛用于研究PDAC的发病机制。然而，鼠标 癌症模型可能忽略了人类和小鼠细胞之间的一些深刻差异。要了解 人PDAC的致瘤机制，我们建立了一种新的分离和遗传学系统 操作来自正常人胰腺组织的原代腺泡细胞和导管细胞。这一独特的系统 为我们提供了研究人类PDAC过程中腺泡或导管细胞最早变化的机会 入会仪式。胰腺炎诱发的腺泡样化生(ADM)被认为是最早的改变 PDAC开发。使用我们的系统，我们在体外重现了腺泡到导管的化生(Adm)。 单细胞水平，证实转化生长因子β信号通路可部分诱导人腺泡细胞产生多药耐药。 通过Smad4介导的途径。在ADM过程中，细胞获得了新的特征属性，包括瞬变 增殖能力。然而，促进这些变化的潜在机制仍不清楚。我们会 使用我们的系统进一步调查ADM流程。KRAS是最早和最频繁的突变 癌基因与胰腺癌的关系。然而，致癌的KRAS引发肿瘤的机制并不是 众所周知，人们普遍认为，需要额外的遗传/表观遗传改变才能 配合KRAS突变启动PDAC开发。我们发现突变的KRAS可以延长 AD细胞(经历了ADM的腺泡细胞)的增殖。我们假设ADM相关的 变化与致癌的KRAS共同启动胰腺癌。尽管Smad4途径是 ADM所必需的，该基因在晚期PDAC样本中频繁突变，表明它可能 不同细胞环境下的不同功能。有趣的是，Smad4缺失的小鼠PDAC模型 发展为导管内乳头状黏液性肿瘤(IPMN)而不是胰腺上皮内肿瘤 (Panin)。无论这一结果是由于老鼠和人类之间的差异还是由于细胞的不同 肿瘤形成的谱系仍有待发现。建议的调查结果 研究将揭示PDAC肿瘤发生的人类特有的方面。这些研究的结果将 不仅提供了发现预后标志的机会，还让我们对PDAC有了深入的了解 肿瘤发生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.