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.

结直肠癌(CRC)在美国的发病率每年近15万例，占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3400名新的 患者被诊断为结直肠癌，其中614人患有晚期疾病，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 治疗靶点和干预策略。上皮性连接功能障碍在结直肠癌中很常见。在早期 重复这一研究计划，我们发现BVES，一种紧密连接相关的蛋白质，是 在结肠肿瘤中通过广泛的启动子高甲基化而低表达，甚至在腺瘤最早阶段也是如此。 我们和其他人进一步证明，恢复BVES的表达可以减弱促肿瘤作用 多种癌细胞株的表型。在之前的资助期间，我们确定了BVES缺陷小鼠 在遗传和化学肿瘤模型中都增加了肿瘤负担和更严重的不典型增生。总而言之， 这些数据表明，BVES在上皮性恶性肿瘤中发挥肿瘤抑制作用；因此，BVES可能 代表了一种新的癌症诊断标记物和/或治疗靶点。从机制上讲，我们开始 理解BVES的功能是作为支架蛋白，协调蛋白质复合体的形成以促进 在信号转导中协调调节细胞内信号通路以改变细胞 对微环境线索作出反应的表型。例如，我们发现BVES与 PR61a：PP2A通过限制LRP6水平来降低细胞c-Myc水平并减弱WNT信号。最近， BVES被发现可以调节心脏中的cAMP信号。我们确定BVES与 AKAP11，一种cAMP/PKA纳米结构域分割蛋白，BVES的丢失与PKA的减少有关 活性表现为CREB的磷酸化程度降低。因此，BVES可能调节另一条信号通路 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是否可以修改已建立的CRC的增长并确定相对贡献 BVES调节的信号转导。在这个提案中，我们构建了三个特定的目标，旨在理解角色 BVES在肿瘤生物学中的应用。首先，我们将加深对BVES：AKAP11：PKA轴的理解。在第二个 目的：探讨体外修复早期肿瘤生物学(腺瘤)的BVES对功能的影响。在 最后，我们将验证恢复BVES可以抑制人结直肠癌生长的假设，并验证 这种BVES的恢复是否使CRC对3D培养和靶向治疗的化疗和靶向治疗敏感 小鼠模型。通过这些研究，我们将获得关于BVES损失是如何贡献的基本见解 恶性进展，并扩展我们对肿瘤相关通路如何调控的知识， 告知新的诊断和治疗方法的发展。

项目成果

AOM/DSS Model of Colitis-Associated Cancer.

• DOI: 10.1007/978-1-4939-3603-8_26
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Parang B;Barrett CW;Williams CS
• 通讯作者: Williams CS

Protein Phosphatase 2A in the Regulation of Wnt Signaling, Stem Cells, and Cancer.

• DOI: 10.3390/genes9030121
• 发表时间: 2018-02-26
• 期刊: Genes
• 影响因子: 3.5
• 作者: Thompson JJ;Williams CS
• 通讯作者: Williams CS

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

• DOI: 10.1136/gutjnl-2015-310255
• 发表时间: 2017-05
• 期刊: Gut
• 影响因子: 24.5
• 作者: Parang B;Kaz AM;Barrett CW;Short SP;Ning W;Keating CE;Mittal MK;Naik RD;Washington MK;Revetta FL;Smith JJ;Chen X;Wilson KT;Brand T;Bader DM;Tansey WP;Chen R;Brentnall TA;Grady WM;Williams CS
• 通讯作者: Williams CS

Pearls of wisdom for aspiring physician-scientist residency applicants and program directors.

• DOI: 10.1172/jci.insight.158467
• 发表时间: 2022-03-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Gallagher EJ;Rockey DC;Kontos CD;Vyas JM;Brass LF;Hu PJ;Isales CM;Ajijola OA;Rathmell WK;Conlin PR;Baiocchi RA;Kazmierczak BI;Akabas MH;Williams CS
• 通讯作者: Williams CS

Selenoproteins in Tumorigenesis and Cancer Progression.

• DOI: 10.1016/bs.acr.2017.08.002
• 发表时间: 2017
• 期刊: Advances in cancer research
• 作者: Short SP;Williams CS
• 通讯作者: Williams CS