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

正常人胰腺组织中胰腺癌发生和进展的机制

• 批准号: 10112846
• 负责人: Pei Wang
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112846
• 关键词: Acinar Cell; Binding; Biological Models; Cancer Model; Cancer cell line; Cell Lineage; Cell Proliferation; Cell model; Cells; Characteristics; Data; Development; Disease; Duct (organ) structure; Ductal Epithelial Cell; Early Diagnosis; Epigenetic Process; Future; Gene Expression; Genes; Genetic; Human; In Vitro; Investigation; Islets of Langerhans Transplantation; KRAS oncogenesis; KRAS2 gene; Lead; Lesion; MADH4 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metaplasia; Metaplastic Cell; Methods; Modeling; Molecular; Morphologic artifacts; Mucinous Neoplasm; Mus; Mutate; Mutation; Neoplasms; Oncogenes; Organoids; Outcome; Outcome Study; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Papillary; Pathogenesis; Pathway interactions; Patients; Play; Process; Prognostic Marker; Property; Role; Sampling; Signal Pathway; Signal Transduction; Stratification; Survival Rate; System; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Transforming Growth Factor beta; cancer cell; cancer initiation; cancer therapy; detection method; diagnostic biomarker; effective therapy; genetic manipulation; improved; innovation; insight; malignant phenotype; mouse model; mutant; neoplastic; novel; pancreatic cancer model; pancreatic ductal adenocarcinoma model; premalignant; promoter; transplant centers; transplant model; tumor; tumor progression; tumorigenesis

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.

正常人胰腺组织中胰腺癌发生和进展的机制 在过去的三十年里，许多癌症的生存率有所提高，但胰腺癌的生存率却有所提高。 由于缺乏早期检测方法和有效的治疗方法，导管腺癌（PDAC）尚未实现这一目标。 转基因小鼠模型已广泛用于研究 PDAC 发病机制。然而，鼠标 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。要了解 人类 PDAC 肿瘤发生机制，我们建立了一个新的系统来分离和遗传 操纵正常人胰腺组织的原代腺泡细胞和导管细胞。这个独特的系统 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 引发。胰腺炎引起的腺泡到导管化生（ADM）被认为是胰腺炎期间最早的变化 PDAC 开发。使用我们的系统，我们在体外重现了腺泡到导管化生 (ADM) 单细胞水平，并确定 TGFβ 信号通路在人腺泡细胞中诱导 ADM，部分 通过 SMAD4 介导的途径。在 ADM 过程中，细胞获得了新的特性，包括瞬态 增殖能力。然而，促进这些变化的潜在机制仍不清楚。我们将 使用我们的系统进一步调查 ADM 流程。 KRAS是最早、最频繁突变的 胰腺癌中的癌基因。然而，致癌 KRAS 引发肿瘤的机制尚不明确。 众所周知，人们普遍认为需要额外的遗传/表观遗传改变 与KRAS突变配合启动PDAC的发育。我们发现突变的 KRAS 可以延长 AD 细胞（经历 ADM 的腺泡细胞）增殖。我们假设 ADM 相关 变化与致癌 KRAS 协同引发胰腺癌。尽管 SMAD4 途径 该基因是 ADM 所需的，在晚期 PDAC 样本中经常发生突变，表明它可能具有 在不同的细胞环境下具有不同的功能。有趣的是，SMAD4 缺失的小鼠 PDAC 模型 发展为导管内乳头状粘液肿瘤（IPMN）而不是胰腺上皮内瘤变 （泛音）。这个结果是由于小鼠和人类之间的差异还是由于细胞不同 肿瘤发展的谱系仍有待发现。拟议的调查结果 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 不仅提供了发现预后标志物的机会，还让我们深入了解 PDAC 肿瘤发生可能导致癌症治疗新方法的开发。