Induced Glycan Alterations in Sub-populations of Pancreatic Tumors

描述（由申请人提供）：已知糖基化改变对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。对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，人们知之甚少。初步数据表明，促炎细胞因子信号传导可诱导胰腺癌细胞中聚糖的改变，提示胰腺癌中常见的炎症环境可能诱导癌细胞改变其细胞外聚糖结构。此外，初步数据表明，不同细胞系组之间诱导的聚糖改变是不同的，这是由与胰腺癌致瘤性相关的细胞表面标记物的存在或缺失所定义的。这一发现表明，诱导的聚糖改变在细胞类型之间是不同的，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。人类原发肿瘤的小鼠异种移植是这项工作的一个很好的系统，它已经被用于胰腺癌，可以为分类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在响应细胞因子信号传导时是否表现出不同的聚糖改变。这个项目的一个重要方面是使用抗体阵列和聚糖检测来测量几种特定蛋白质上的蛋白质和聚糖变化的独特实验方法。该试验的微尺度性质对于研究细胞的小亚群也很有价值。这项工作非常适合试点项目机制，因为它将为可能的变革性研究方向提供见解。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的进展很重要，但引起这些改变的因素，以及它们出现的特定癌细胞类型，还不完全清楚。这项提议解决了这个问题，这对治疗或控制胰腺癌具有重要意义。

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.