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）在美国的发病率约为每年15万例，占10%以上

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