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: 10620135
• 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/10620135
• 关键词: A kinase anchoring protein; Adrenergic Agents; Affect; Anchorage-Independent Growth; Animal Model; Attenuated; Binding; Biology; Blood Vessels; CREB1 gene; Cancer Biology; Cancer Etiology; Cancer Model; 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 Attachment; Epithelium; 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; Phosphorylation; Polyps; Positioning Attribute; Primary Neoplasm; Process; Prognosis; Proliferating; 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; Therapeutic Intervention; Tight Junctions; Tumor Biology; Tumor Burden; Tumor Suppressor Proteins; Veterans; Veterans Health Administration; WNT Signaling Pathway; Work; Xenograft procedure; adenoma; advanced disease; anticancer research; attenuation; c-myc Genes; cancer diagnosis; cancer survival; 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; nano; new therapeutic target; novel; novel diagnostics; novel therapeutics; potassium channel protein TREK-1; premalignant; promoter; protein complex; receptor; receptor density; response; restoration; screening program; sensor; targeted treatment; therapeutic target; three dimensional cell culture; transcriptome sequencing; treatment response; tumor; tumor growth; tumor initiation; tumor progression; 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.

美国结直肠癌 (CRC) 的发病率每年近 15 万例，占 10% 以上 2016 年，仅退伍军人管理局医疗系统内就有 3,400 例新诊断癌症。 患者被诊断患有结直肠癌，其中 614 名患者已处于晚期疾病且治疗选择非常有限。 了解潜在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早期很常见。 通过迭代该研究计划，我们发现 BVES（一种紧密连接相关蛋白） 即使在最早的腺瘤阶段，结肠肿瘤中由于广泛的启动子高甲基化而表达不足。 我们和其他人进一步证明，恢复 BVES 表达可以减弱促肿瘤发生作用。 在之前的资助期间，我们确定了 BVES 缺陷小鼠的表型。 总的来说，在遗传和化学肿瘤模型中，肿瘤负荷增加，发育不良更严重。 这些数据表明，BVES 在上皮恶性肿瘤中发挥肿瘤抑制作用；因此，BVES 可能是一种肿瘤抑制因子。 从机制上讲，我们开始研究癌症的新诊断标记物和/或治疗靶点。 了解 BVES 作为支架蛋白发挥作用，协调蛋白质复合物的形成以促进 external ® 参与信号转导，协调调节细胞内信号通路，从而改变细胞 例如，我们发现 BVES 与微环境相互作用。 PR61a:PP2A 通过限制 LRP6 水平来降低细胞 c-Myc 水平并减弱 WNT 信号传导。 我们发现 BVES 可以调节心脏中的 cAMP 信号传导。 AKAP11，一种 cAMP/PKA 纳米结构域分配蛋白，BVES 损失与 PKA 减少相关 磷酸化 CREB ​​活性降低因此，BVES 可能调节另一个信号通路。 最后，我们建立了 II 期和 III 期人类 CRC 3D 培养物库。 并开发了对它们进行基因改造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 的增长并确定相对贡献 在本提案中，我们构建了三个旨在理解其作用的具体目标。 首先，我们将进一步了解 BVES:AKAP11:PKA 轴。 目的是确定恢复 BVES 对离体早期肿瘤生物学（腺瘤）的功能影响。 最后一个目标，我们将检验恢复 BVES 可以减弱人类 CRC 生长的假设并检验 这种恢复 BVES 是否会使 CRC 对 3D 培养中的化疗和靶向治疗敏感，以及 通过这些研究，我们将获得关于 BVES 损失如何影响的基本见解。 恶性进展并扩展我们对肿瘤相关途径如何调节的知识， 为新诊断和治疗方法的开发提供信息。

项目成果

Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut.

硒蛋白和氧化应激诱导肠道炎症肿瘤发生。

• 发表时间: 2017-02
• 作者: Barrett, Caitlyn W;Short, Sarah P;Williams, Christopher S
• 通讯作者: Williams, Christopher S

Selenoproteins in Tumorigenesis and Cancer Progression.

肿瘤发生和癌症进展中的硒蛋白。

• 发表时间: 2017
• 作者: Short, Sarah P;Williams, Christopher S
• 通讯作者: Williams, Christopher S

BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.

BVES 调节放疗后肠道干细胞程序和肠隐窝活力。

• 发表时间: 2016
• 作者: Reddy, Vishruth K;Short, Sarah P;Barrett, Caitlyn W;Mittal, Mukul K;Keating, Cody E;Thompson, Joshua J;Harris, Elizabeth I;Revetta, Frank;Bader, David M;Brand, Thomas;Washington, M Kay;Williams, Christopher S
• 通讯作者: Williams, Christopher S

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.

BVES 通过 PP2A 调节 c-Myc 稳定性并抑制结肠炎诱导的肿瘤发生。

• 发表时间: 2017
• 影响因子: 24.5
• 作者: Parang, Bobak;Kaz, Andrew M;Barrett, Caitlyn W;Short, Sarah P;Ning, Wei;Keating, Cody E;Mittal, Mukul K;Naik, Rishi D;Washington, Mary K;Revetta, Frank L;Smith, J Joshua;Chen, Xi;Wilson, Keith T;Brand, Thomas;Bader, David M;Tansey, William
• 通讯作者: Tansey, William

The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.

转录辅阻遏物 MTGR1 调节肠道分泌谱系分配。

• 发表时间: 2015-03
• 作者: Parang, Bobak;Rosenblatt, Daniel;Williams, Amanda D;Washington, Mary K;Revetta, Frank;Short, Sarah P;Reddy, Vishruth K;Hunt, Aubrey;Shroyer, Noah F;Engel, Michael E;Hiebert, Scott W;Williams, Christopher S
• 通讯作者: Williams, Christopher S