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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

基本信息

批准号：
10363688
负责人：
Pei Wang
金额：
$ 15.22万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363688
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 prognosis biomarker promoter transplant centers transplant model tumor tumor progression tumorigenesis

项目摘要

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.

正常人类胰腺组织胰腺癌发生和发展的机制