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

摘要 胰腺癌(PDAC)是一种致命性疾病，是全世界与癌症相关的死亡的第四大原因。 美国。在与癌症相关的死亡中，90%是由转移造成的。MUC16的表达(50-60%) 与转移性胰腺癌高度相关。我们最近发现与癌症相关的亚型 具有生物活性：癌症相关形式的MUC16糖蛋白含有 高亲和力的表皮生长因子受体(EGFR_1、2、3)和整合素(α_4/β_1)多价配体 复合体，导致包括Akt和FAK在内的信号级联的结构性激活和 随之而来的是胰腺癌细胞的致癌潜能增加。有趣的是，这些活动 由MUC16的异常(截短)O-糖基化增强。这一发现与我们最近的 有关MUC16在转移性胰腺癌中广泛表达的文献表明，在 除了作为腺癌的生物标志物外，MUC16还可以作为致癌细胞因子或 生长因子。此外，对临床样本的全基因组分析显示，MUC16是 在胰腺癌中突变最多的基因之一。因此，除了作为生物标志物之外， 腺癌，我们假设肿瘤相关和突变形式的循环CA125/MUC16 具有作为可能有助于旁分泌致癌信号的生长因子或细胞因子的生物学作用 可能与肿瘤进展和肿瘤继发效应有关的远处器官部位的相互作用 成长。我们的长期目标是确定MUC16的分子和生物学机制 介导肿瘤的侵袭性、进展、早期转移和癌症进展的全身效应。至 要做到这一点，我们建议调查位置特异性突变有助于激活的假设 MUC16的生物活性异构体和/或蛋白水解性切割，并评价其在细胞内的生物活性 以胰腺癌模型为基础(目标1)。我们将研究突变的MUC16对肿瘤的贡献 活体原位胰腺肿瘤模型系统的进展(目标2)。我们将确定 MUC16基因突变，并研究其在胰腺癌临床标本中的生物学功能(目的3)。 这些研究将使人们对分泌的肿瘤产品的功能和影响有一个新的理解 肿瘤生长、远处器官转移、肿瘤微环境构型的生物标志物 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.