Project 2: Biological Effects of Patient-derived Mutations in MUC16 on PC Metastasis

摘要 胰腺癌（PDAC）是一种致死性疾病，是美国癌症相关死亡的第四大原因。 美国的转移是90%的癌症相关死亡的原因。MUC 16的表达（50-60%） 与转移性胰腺癌高度相关。我们最近发现癌症相关的同种型 具有生物活性：癌症相关形式的MUC 16糖蛋白含有 对表皮生长因子受体（EGFR 1、2和3）和整联蛋白（α4/β1）具有高亲合力的多价配体 复合物，其导致包括Akt和FAK的信号级联的组成性激活， 胰腺癌细胞的致癌潜力也随之增加。有趣的是，这些活动 通过MUC 16的异常（截短的）O-糖基化增强。这一发现加上我们最近的 MUC 16在转移性胰腺癌中广泛表达的文献表明， 除了用作腺癌的生物标志物之外，MUC 16还可以用作致癌细胞因子， 生长因子此外，PDAC的临床样品的全基因组分析已经揭示MUC 16是 是胰腺癌中最高度突变的基因之一。因此，除了作为生物标志物， 腺癌，我们假设肿瘤相关和突变形式的循环CA 125/MUC 16 具有作为生长因子或细胞因子的生物学作用，可能有助于旁分泌致癌信号传导 可能导致肿瘤进展和肿瘤继发效应的远端器官部位相互作用 增长我们的长期目标是确定MUC 16在细胞内表达的分子和生物学机制。 介导肿瘤侵袭性、进展、早期转移和癌症进展的全身效应。到 实现这一点，我们建议调查的假设，位点特异性突变有助于激活 生物活性同种型和/或MUC 16的蛋白水解切割，并评估细胞中的生物活性 基于胰腺癌的模型（目的1）。我们将研究突变的MUC 16对肿瘤的贡献， 在体内原位胰腺肿瘤模型系统中的进展（Aim 2）。我们将确定 目的3：研究MUC 16基因突变对胰腺癌临床标本的生物学功能的影响。 这些研究将导致对分泌的肿瘤产物的功能和作用的新理解， 肿瘤生长、远处器官转移、肿瘤微环境结构的生物标志物 以及肿瘤进展的其他方面。

Abstract Pancreatic adenocarcinoma (PDAC) is a lethal disease, the fourth-leading cause of cancer-related death in the United States. Metastasis is responsible for 90% of the cancer-related deaths. Expression of MUC16 (50-60%) is highly associated with metastatic pancreatic cancer. We recently discovered that cancer associated isoforms of CA125/MUC16 have biological activity: cancer associated forms of the MUC16 glycoprotein contain multivalent ligands with high avidity for epidermal growth factor receptor (EGFR1, 2 and 3) and integrin (α4/β1) complexes, which results in constitutive activation of signaling cascades that include Akt and FAK and concomitant increases in the oncogenic potential of pancreatic cancer cells. Interestingly, these activities were enhanced by aberrant (truncated) O-glycosylation of MUC16. This finding together with our recent documentation of the widespread expression of MUC16 in metastatic pancreatic cancer, suggest that in addition to serving as a biomarker for adenocarcinoma, MUC16 can function as an oncogenic cytokine or growth factor. Further, whole genome analyses of clinical samples of PDAC have revealed that MUC16 is among the most highly mutated genes in pancreatic cancer. Hence, in addition to serving as a biomarker for adenocarcinomas, we hypothesize that tumor associated and mutated forms of circulating CA125/MUC16 have biological roles as a growth factor or cytokines that may contribute to paracrine oncogenic signaling interactions in the distant organ sites that may contribute to tumor progression and secondary effects of tumor growth. Our long term goal is to determine the molecular and biological mechanisms by which MUC16 mediates tumor aggressiveness, progression, early metastasis and systemic effects of cancer progression. To achieve this, we propose to investigate the hypothesis that site specific mutation contributes to activation of biologically active isoforms and/or proteolytic cleavage of MUC16, and evaluate the biological activity in cell based models of pancreatic cancer (Aim 1). We will investigate contribution of mutated MUC16 to tumor progression in an in vivo orthotopic pancreas tumor model system (Aim 2). We will determine the sites of mutation on MUC16, and investigate its biological functions in clinical specimens of pancreatic cancer (Aim 3). These studies will lead to a new understanding of the function and effects of secreted tumor products that are biomarkers on tumor growth, metastasis to distant organ sites, configuration of the tumor microenvironment and other aspects of tumor progression.