ST6Gal-1 contributes to pancreatic cancer initiation by promoting pancreatitis-induced acinar to ductal metaplasia

ST6Gal-1 通过促进胰腺炎诱导的腺泡向导管化生促进胰腺癌的发生

• 批准号: 10672415
• 负责人: Michael Marciel
• 金额: $ 7.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672415
• 关键词: Acceleration; Acinar Cell; Acute; Apoptosis; Apoptotic; Attention; Binding; Cancer Etiology; Caspase; Cell Survival; Cell membrane; Cells; Cessation of life; Characteristics; Charge; Chronic; Coupled; Data; Development; Duct (organ) structure; Ductal Epithelial Cell; Dysplasia; Endowment; Enzymes; Epidermal Growth Factor Receptor; Epithelium; Event; Exposure to; Genes; Golgi Apparatus; Human; Individual; Inflammation; Inflammatory; KRAS oncogenesis; KRAS2 gene; KRASG12D; Knockout Mice; Lesion; Link; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane; Metaplasia; Modeling; Molecular; Molecular Target; Mus; Mutation; NF-kappa B; Neoplasms; Neoplastic Cell Transformation; Oncogenes; Oncogenic; Organoids; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Premalignant Cell; Process; Prognosis; Property; Protein Glycosylation; Proteins; Reporting; Resistance; Risk; Role; Sialic Acids; Sialyltransferases; Signal Transduction; Signaling Molecule; Stimulus; Stress; Structure; Sugar Acids; Surface; TNF gene; TNFRSF1A gene; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Transgenic Mice; Tumor Necrosis Factor Receptor; United States; Up-Regulation; biomarker identification; cancer initiation; cancer stem cell; carcinogenesis; cell transformation; chronic pancreatitis; differential expression; early detection biomarkers; effective therapy; glycosylation; innovation; inorganic phosphate; metaplastic cell transformation; mortality; mouse model; neoplastic; novel; novel therapeutics; overexpression; receptor; senescence; sialylation; stem; stem-like cell; transcription factor; transdifferentiation; tumor; tumor initiation

Project Summary This project will elucidate a novel mechanism by which chronic pancreatitis leads to pancreatic adenocarcinoma, with a specific focus on one of the earliest neoplastic events, acinar to ductal metaplasia (ADM). We have identified a new enzyme, ST6Gal1, that is involved in both pancreatitis and pancreatic adenocarcinoma. ST6Gal1 is a membrane bound golgi sialyltransferase that adds sialic acid, in an α2-6 linkage, to N-glycosylated proteins that are destined for the plasma membrane. ST6Gal1 has been shown to endow cells with cancer stem cell (CSC)-like properties including greater tumor initiating potential and enhanced resistance to apoptosis through TNFR1/NFκB signaling axis. To study the role of ST6Gal1 in pancreatic cancer, we generated a transgenic mouse line with ST6Gal1 overexpression (ST6-OE) exclusively in the pancreas and crossed these mice to a pancreatic ductal adenocarcinoma (PDAC) mouse model (KC mice) to generate KC mice with ST6-OE in the pancreas (KC-ST6-OE mice). Compared to KC mice (median survival = 13.6 mo) KC-ST6-OE mice demonstrate accelerated mortality (median survival = 4.3 mo). The accelerated pathogenesis observed when ST6Gal1 expression is forced suggests that ST6Gal1 may prime the cells for transformation. These findings led us to examine if ST6Gal1 upregulation in premalignant cells can promote neoplasia. IHC analysis of human chronic pancreatitis tissue arrays demonstrated an increase in ST6Gal1 expression in ADM lesions and co-expression of the stem/ductal transcription factor, Sox9. Therefore, we hypothesize that during pancreatitis-induced inflammation, ST6Gal1 expression promotes acinar cell survival and thus primes the cell for transformation. To test this hypothesis, we ask the following: i) Does ST6Gal1 promote cell survival following inflammatory damage and promote ADM formation? ii) Given that STGal1 enhances both basal and TNF-dependent TNFR1/NFkB signaling, does ST6Gal1 imparts stem/ductal characteristics through activating a TNFR1-NFκB-Sox9 pathway? iii) Does ST6Gal1 prime cells for KRAS driven transformation (>90% of PDAC patients display KRAS mutation)? iv) Does ST6Gal1 promote the transition from ADM-lesions into Pancreatic intraepithelial neoplasias (PanINs)? The findings from this study may lead to the identification of biomarkers that report whether neoplastic transformation has occurred and lead to therapeutics that can delay or suppress this transition.

项目摘要 该项目将阐明一种新的机制，慢性胰腺炎导致胰腺腺癌， 特定的重点是最早的肿瘤事件之一，腺泡到导管化生（ADM）。我们有 确定了一种新酶ST6GAL1，该酶涉及胰腺炎和胰腺腺癌。 ST6GAL1是 在α2-6链接中添加唾液酸的膜结合的Golfi siAllyltransferase，以N-糖基化蛋白 注定质膜。 ST6GAL1已显示可赋予癌细胞（CSC）样细胞样细胞 包括更大肿瘤在内的特性启动潜力和通过TNFR1/NFκB对凋亡的抗性增强 信号轴。为了研究ST6GAL1在胰腺癌中的作用，我们用ST6GAL1产生了转基因小鼠系 专门在胰腺中的过表达（ST6-OE），并将这些小鼠越过胰腺导管腺癌 （PDAC）小鼠模型（KC小鼠）在胰腺中用ST6-OE生成KC小鼠（KC-ST6-OE小鼠）。比较的 对于KC小鼠（中位存活= 13.6 mo）KC-ST6-OE小鼠表现出加速死亡率（中位生存率= 4.3 mo）。当迫使ST6GAL1表达时观察到的加速发病机理表明ST6GAL1可能会质量 转化的细胞。这些发现使我们检查了prodaparignant细胞中的ST6GAL1是否可以 促进肿瘤。人类慢性胰腺炎组织阵列的IHC分析表明ST6GAL1有所增加 茎/导管转录因子SOX9中的ADM病变和共表达。因此，我们假设 在胰腺炎诱导的注射过程中，ST6GAL1表达促进腺泡细胞的存活，从而素质 用于转化的单元。要检验该假设 炎症损害并促进ADM形成？ ii）鉴于STGAL1增强了基本和TNF的依赖性 TNFR1/NFKB信号传导，通过激活TNFR1-NFκB-SOX9，ST6GAL1赋予茎/导管特性 路径？ iii）do st6gal1用于KRAS驱动转化的主要细胞（> 90％的PDAC患者显示KRAS 突变）？ iv）do st6gal1促进了从add肿块向胰腺内肿瘤的过渡 （Panins）？这项研究的发现可能导致鉴定生物标志物，以报告肿瘤 转化发生了，并导致可以延迟或抑制这种过渡的治疗。