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.

结直肠癌（CRC）在美国的发病率几乎为每年15万例，占总发病率的10%以上。 新的癌症诊断。2016年，仅在退伍军人管理局医疗保健系统内，就有3,400名新的 患者被诊断为CRC，包括614例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恶性转化的关键。 治疗目标和干预策略。上皮连接功能障碍在结直肠癌中很常见。月初 在这项研究计划的迭代中，我们发现BVES，一种紧密连接相关蛋白， 在结肠肿瘤中，甚至在最早的腺瘤阶段，通过广泛的启动子超甲基化而低表达。 我们和其他人已经进一步证明，恢复BVES表达减弱了促肿瘤发生作用。 在多种癌细胞系中的表型。在之前的资助期间，我们确定BVES缺陷小鼠 在遗传和化学肿瘤模型中，肿瘤负荷增加，发育异常更严重。总的来说， 这些数据表明BVES在上皮恶性肿瘤中起肿瘤抑制作用;因此，BVES可能 代表癌症中新的诊断标志物和/或治疗靶点。机械地，我们开始 了解BVES作为支架蛋白的功能，协调蛋白质复合物的形成，以促进 outside ®在信号转导中协调调节细胞内信号传导途径，以改变细胞 表型对微环境线索的反应。例如，我们发现BVES与 PR 61 a：PP 2A通过限制LRP 6水平来降低细胞c-Myc水平并减弱WNT信号传导。最近， BVES被发现可以调节心脏中的cAMP信号。我们确定BVES与 AKAP 11是一种cAMP/PKA纳米结构域分配蛋白，BVES损失与PKA减少相关。 通过减少的磷酸化CREB证明活性。因此，BVES可能调节另一个信号通路 与肿瘤生物学高度相关。最后，我们建立了第二阶段和第三阶段人类CRC 3D培养物库 并开发了基因修饰和原位异种移植的技术。这将作为一个平台， 用于测试BVES是否可以改变已建立的CRC的生长并确定相对贡献 BVES调节信号的机制在本建议中，我们构建了三个具体目标，旨在了解角色 BVES在肿瘤生物学中的应用首先，我们将进一步了解BVES：AKAP 11：PKA轴。在第二 目的是，我们将确定离体恢复BVES对早期肿瘤生物学（腺瘤）的功能影响。在 最后，我们将测试恢复BVES可以减弱人CRC生长的假设，并测试 在3D培养中，这种恢复BVES是否使CRC对化疗和靶向治疗敏感， 鼠模型。通过这些研究，我们将获得基本的见解如何BVES损失贡献 并扩展我们对肿瘤相关通路如何调节的知识， 为新的诊断和治疗方法的开发提供信息。