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

项目 2：MUC16 患者源性突变对 PC 转移的生物学影响

• 批准号: 10413939
• 负责人: Michael A. Hollingsworth
• 金额: $ 31.01万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413939
• 关键词: Adenocarcinoma; Affect; Autopsy; Avidity; Binding; Biological; Biological Markers; Biological Models; Biological Process; CA-125 Antigen; CRISPR/Cas technology; Cancer Etiology; Cancer cell line; Cell surface; Cells; Cessation of life; Clinical; Complex; Data; Disease; Disease Progression; Disease remission; Distant; Documentation; EGFR gene; Epidermal Growth Factor Receptor; Event; Extracellular Domain; Genes; Genetic Engineering; Glycoproteins; Goals; Growth Factor; Growth Factor Receptors; Incidence; Integrin Binding; Integrin alpha4; Integrin alpha4beta1; Integrins; Lead; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Molecular; Monitor; Mucins; Mutate; Mutation; Neoplasm Metastasis; Nonmetastatic; Normal tissue morphology; Oncogenic; Organ; Organ failure; PTK2 gene; Pancreatic Adenocarcinoma; Paracrine Communication; Patients; Polysaccharides; Primary Neoplasm; Property; Protein Isoforms; Proteins; Recombinants; Reporting; Role; Sampling; Signal Pathway; Signal Transduction; Site; Specimen; Structure; Surveys; Testing; Tumor Antigens; Tumor Markers; United States; Vertebral column; autocrine; base; cytokine; genome analysis; glycosylation; in vivo; novel; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; paracrine; receptor; tumor; tumor growth; tumor microenvironment; tumor progression; whole genome

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.

抽象的 胰腺癌（PDAC）是一种致命性疾病，是癌症相关死亡的第四大原因 美国，90% 的癌症相关死亡是由转移引起的（50-60%）。 我们最近发现癌症相关亚型与转移性胰腺癌高度相关。 CA125/MUC16 具有生物活性：癌症相关形式的 MUC16 糖蛋白含有 对表皮生长因子受体（EGFR1、2 和 3）和整合素（α4/β1）具有高亲和力的多价配体 复合物，导致包括 Akt 和 FAK 在内的信号级联的组成型激活 胰腺癌细胞的致癌潜力随之增加。 MUC16 的异常（截短）O-糖基化增强了这一发现以及我们最近的发现。 MUC16 在转移性胰腺癌中广泛表达的文献表明， 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 此外，PDAC 临床样本的全基因组分析表明，MUC16 是生长因子。 因此，它除了可以作为胰腺癌的生物标志物之外，也是胰腺癌中突变程度最高的基因之一。 腺癌，我们追踪循环 CA125/MUC16 的肿瘤相关和突变形式 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 远处肿瘤器官部位的相互作用可能有助于肿瘤的进展和继发效应 我们的长期目标是确定 MUC16 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。 为了实现这一目标，我们建议研究位点特异性突变有助于激活 MUC16 的生物活性异构体和/或蛋白水解裂解，并评估细胞中的生物活性 我们将研究突变的 MUC16 对肿瘤的贡献。 体内原位胰腺肿瘤模型系统中的进展（目标 2）。 MUC16 突变，并研究其在胰腺癌临床标本中的生物学功能（目标 3）。 这些研究将导致人们对分泌性肿瘤产物的功能和作用有新的认识。 肿瘤生长、远处器官转移、肿瘤微环境配置的生物标志物 以及肿瘤进展的其他方面。