Modulation of Junctional Signaling by BVES in Colorectal Carcinoma

BVES 对结直肠癌中连接信号的调节

• 批准号: 10392341
• 负责人: Christopher S. Williams
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392341
• 关键词: 3-Dimensional; A kinase anchoring protein; Adrenergic Agents; Affect; Anchorage-Independent Growth; Animal Model; Attenuated; Binding; Biology; Blood Vessels; CREB1 gene; Cancer Biology; Cancer Etiology; Cancer cell line; Cell membrane; Cells; Cessation of life; Chemicals; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complex; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diagnosis; Disease; Epithelial; Epithelial Attachment; Foundations; Functional disorder; Funding; Gene Expression; Genetic; Grant; Growth; Healthcare Systems; Heart; Human; Hypermethylation; Incidence; Inflammatory; Intervention; Knowledge; Large Intestine Carcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Modeling; Morphology; Mus; Muscle Cells; Neoplasm Metastasis; Organoids; Pathway interactions; Patients; Phenotype; Phosphotransferases; Polyps; Positioning Attribute; Primary Neoplasm; Process; Prognosis; Protein phosphatase; Proteins; Regulation; Research; Role; Scaffolding Protein; Severe dysplasia; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stage at Diagnosis; Structure; System; Techniques; Testing; Therapeutic Intervention; Tight Junctions; Tumor Biology; Tumor Burden; Tumor Suppressor Proteins; United States Department of Veterans Affairs; Veterans; WNT Signaling Pathway; Work; Xenograft procedure; adenoma; advanced disease; anticancer research; attenuation; base; c-myc Genes; cancer diagnosis; cancer type; cell motility; chemotherapy; clinically relevant; colorectal cancer screening; design; diagnostic biomarker; improved; inorganic phosphate; insight; intestinal epithelium; malignant breast neoplasm; malignant stomach neoplasm; monolayer; mortality; mouse model; new therapeutic target; novel; novel diagnostics; novel therapeutics; potassium channel protein TREK-1; premalignant; promoter; protein complex; receptor density; response; restoration; screening program; sensor; targeted treatment; therapeutic target; three dimensional cell culture; transcriptome sequencing; treatment response; tumor; tumor growth; tumor initiation; tumorigenesis; tumorigenic

Colorectal cancer (CRC) has a U.S. incidence rate of almost 150,000 cases per year, encompassing over 10% of new cancer diagnoses. In 2016, within the Veterans Administration Healthcare System alone, 3,400 new patients were diagnosed with CRC, including 614 with advanced disease and very limited treatment options. Understanding the basic biology of the underlying malignant transformation is the key to identifying new therapeutic targets and intervention strategies. Epithelial junctional dysfunction is common in CRC. In early iterations of this research plan, we discovered that BVES, a tight junction-associated protein, was underexpressed via extensive promoter hypermethylation in colonic tumors, even at the earliest adenoma stage. We and others have further demonstrated that restoring BVES expression attenuated pro-tumorigenic phenotypes in a variety of cancer cell lines. In the prior funding period, we determined that BVES-deficient mice had increased tumor burden and more severe dysplasia in both genetic and chemical tumor models. Collectively, these data suggested that BVES functions as a tumor suppressor in epithelial malignancy; thus, BVES may represent a new diagnostic marker and/or therapeutic target in cancer. Mechanistically, we are beginning to understand that BVES functions as a scaffolding protein, orchestrating protein complex formation to facilitate outside ® in signal transduction to coordinately regulate intracellular signaling pathways to alter cellular phenotypes in response to microenvironmental cues. For example, we discovered that BVES interacts with PR61a:PP2A to reduce cellular c-Myc levels and attenuate WNT signaling by restricting LRP6 levels. Recently, BVES was discovered to modulate cAMP signaling in the heart. We determined that BVES interacts with AKAP11, a cAMP/PKA nanodomain partitioning protein, and that BVES loss was associated with reduced PKA activity as evidenced by reduced phosphorylated CREB. Thus, BVES likely regulates another signaling pathway highly relevant to tumor biology. Lastly, we have established a bank of Stage II and III human CRC 3D cultures and developed techniques to genetically modify and orthotopically xenograft them. This will serve as a platform for testing whether BVES can modify the growth of established CRC and determining the relative contributions of BVES-regulated signaling. In this proposal, we structure three Specific Aims designed to understand the role of BVES in tumor biology. First, we will further our understanding of the BVES:AKAP11:PKA axis. In the second aim, we will determine the functional impact of restoring BVES in early tumor biology (adenomas) ex vivo. In the last aim, we will test the hypothesis that restoring BVES can attenuate the growth of human CRC and test whether this restoring BVES sensitizes CRC to chemotherapeutic and targeted therapies in 3D culture and murine models. Through these studies, we will gain fundamental insights into how BVES loss contributes to malignant progression and extend our knowledge of how tumor-relevant pathways are regulated, informing development of new diagnostics and therapeutics.

大肠癌（CRC）的发病率每年近15万例，涵盖超过10％ 新的癌症诊断。 2016年，仅在退伍军人管理系统中，有3,400个新的 患者被诊断出患有CRC，包括614例患有晚期疾病和非常有限的治疗选择。 了解潜在的恶性转化的基本生物学是识别新的关键 治疗目标和干预策略。上皮连接功能障碍在CRC中很常见。在早期 该研究计划的迭代，我们发现BVE是一种紧密的连接相关蛋白，是 即使在最早的腺瘤阶段，也无法通过大量启动子高甲基化的高甲基化来进行。 我们和其他其他 多种癌细胞系中的表型。在以前的资金期间，我们确定BVE缺乏小鼠 在遗传和化学肿瘤模型中，肿瘤伯嫩和更严重的发育不良增加。共同 这些数据表明，BVE在上皮恶性肿瘤中充当肿瘤抑制剂。因此，BVE可能 代表癌症中新的诊断标记和/或热靶标。从机械上讲，我们开始 理解BVE充当脚手架蛋白质，策划蛋白质复合物的形成以促进 外部®在信号转导中以协调调节细胞内信号通路以改变细胞 响应微环境提示的表型。例如，我们发现BVE与 PR61A：PP2A通过限制LRP6水平降低细胞C-MYC水平并减轻Wnt信号传导。最近， 发现BVE被发现调节心脏中的营地信号。我们确定BVE与 AKAP11，营地/PKA纳米域分配蛋白，而BVE损失与PKA减少有关 磷酸化的CREB降低证明了活性。这，BVE可能调节另一个信号通路 与肿瘤生物学高度相关。最后，我们建立了II期和III期人CRC 3D文化的库 并开发了遗传修饰和原始异种移植的技术。这将用作平台 用于测试BVE是否可以修改已建立的CRC的增长并确定相对贡献 BVES调节的信号传导。在此提案中，我们构建了三个旨在了解角色的特定目标 肿瘤生物学中的BVE。首先，我们将进一步了解BVE：AKAP11：PKA轴。在第二个 目的，我们将确定恢复BVE早期肿瘤生物学（腺瘤）的功能影响。在 最后一个目标，我们将检验以下假设：恢复BVE可以减弱人类CRC的生长和测试 这种恢复BVE是否会在3D培养和 鼠模型。通过这些研究，我们将获得有关BVE损失如何贡献的基本见解 为恶性发展并扩展我们对如何调节肿瘤相关途径的了解， 告知新诊断和治疗的发展。