Induced Glycan Alterations in Sub-populations of Pancreatic Tumors

描述（由申请人提供）：已知聚糖改变对于促进癌症进展的几个过程至关重要，特别是在糖基化改变非常普遍的胰腺癌中。关于引起这些改变的条件，或者它们是否明显发生在特定的癌细胞亚群中，我们知之甚少。初步数据显示，促炎细胞因子信号传导诱导胰腺癌细胞中的聚糖改变，这表明胰腺癌中常见的炎症环境诱导癌细胞修饰其细胞外聚糖结构的可能性。此外，初步数据表明，诱导的聚糖改变在细胞系组之间是不同的，如通过存在或不存在与胰腺癌致瘤性相关的细胞表面标志物所定义的。这一发现表明，诱导的聚糖改变在细胞类型之间是不同的，并且这些聚糖改变有助于每种细胞类型的特定行为。为了深入了解这些行为与癌症生物学的相关性，下一步是在原发性肿瘤细胞中研究这些假设，而不是在用于初步研究的细胞系模型中。这项工作的一个很好的系统是来自人类原发性肿瘤的小鼠异种移植物，这已经建立了胰腺癌，可以为分选细胞亚群的实验提供足够的材料。在第一个目标中，我们将确定几种粘蛋白的糖基化或表达状态在致瘤性和非致瘤性亚群之间是否不同。在第二个目标中，我们将确定这些亚群是否响应于细胞因子信号传导而显示不同的聚糖改变。该项目的一个重要方面是使用具有聚糖检测的抗体阵列来测量几种特定蛋白质的蛋白质和聚糖变化的独特实验方法。该测定的微尺度性质对于研究小的细胞亚群也是有价值的。这项工作非常适合试点项目机制，因为它将使人们深入了解一个可能具有变革意义的研究方向。公共卫生相关性：胰腺癌是一种生存率极低的毁灭性疾病。众所周知，癌细胞表面碳水化合物的改变对疾病进展很重要，但引起这些改变的因素以及它们出现的特定癌细胞类型并不完全清楚。这项提案解决了这个问题，这对治疗或控制胰腺癌有影响。

DESCRIPTION (provided by applicant): Glycan alterations are known to be critical for several processes that contribute to cancer progression, particularly in pancreatic cancer, where glycosylation alterations are highly prevalent. Little is known about the conditions that give rise to those alterations, or whether they distinctly occur in particular subpopulations of cancer cells. Preliminary data have shown that pro-inflammatory cytokine signaling induces glycan alterations in pancreatic cancer cells, suggesting the possibility that the inflammatory environment typically seen in pancreatic cancer induces cancer cells to modify their extracellular glycan structures. Furthermore, the preliminary data suggest that the induced glycan alterations are different between groups of cell lines, as defined by the presence or absence of cell-surface markers that are associated with tumorigenicity in pancreatic cancer. That finding suggests that induced glycan alterations are distinct between cell types, and that these glycan alterations contribute to the particular behavior of each cell type. In order to gain insight into the relevance of these behaviors to cancer biology, the next step is to investigate these hypotheses in primary tumor cells, rather than in the cell line models used for the preliminary studies. A good system for that work is mouse xenografts from human primary tumors, which have been established for pancreatic cancer and can provide enough material for experiments on sorted cell subpopulations. In the first aim, we will determine whether the glycosylation or expression status of several mucins is different between the tumorigenic and non-tumorigenic subpopulations. In the second aim, we will determine whether these subpopulations display different glycan alterations in response to cytokine signaling. A significant aspect of this project is the unique experimental approach of using antibody arrays with glycan detection to measure protein and glycan variation on several specific proteins. The micro-scale nature of that assay also is valuable for the study of small subpopulations of cells. This work is well suited to a pilot-project mechanism since it will give insights into a possibly transformative research direction. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease with very low survival rates. It is known that alterations to the carbohydrates on the surfaces of cancer cells are important for disease progression, but the factors that give rise to those alterations, and the particular cancer cell types on which they appear, are incompletely understood. This proposal addresses that question, which has implications for treating or controlling pancreatic cancer.