BVES modulation of intestinal homeostasis and tumorigenesis via regulation of Wnt signaling

BVES 通过调节 Wnt 信号传导调节肠道稳态和肿瘤发生

• 批准号: 9190648
• 负责人: Joshua James Thompson
• 金额: $ 2.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190648
• 关键词: Accounting; Affect; Anchorage-Independent Growth; Animal Model; Attenuated; Automobile Driving; Blood Vessels; Cadherins; Cancer cell line; Cancerous; Cell Adhesion Molecules; Cell Communication; Cell Nucleus; Cell Proliferation; Cell membrane; Cell physiology; Cells; Clonal Expansion; Colon Carcinoma; Colorectal Cancer; Competence; Complementary DNA; Complex; Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Epithelial; Gene Targeting; Goals; Growth; Heart; Homeostasis; Human; Individual; Inflammatory; Intervention; Intestines; Knockout Mice; Laboratories; Lead; Link; Literature; Maintenance; Malignant Neoplasms; Membrane; Mesenchymal; Molecular; Mus; Mutation; Neoplasm Metastasis; Nuclear; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Protein phosphatase; Proteins; Regulation; Reporter; Research; Role; Rotation; Signal Pathway; Signal Transduction; Stem cells; Testing; Tight Junctions; Translating; Treatment Efficacy; Tumor Biology; Up-Regulation; beta catenin; c-myc Genes; cancer diagnosis; carcinogenesis; cell growth; cell motility; human disease; intestinal crypt; intestinal homeostasis; molecular targeted therapies; monolayer; mouse model; new therapeutic target; novel; overexpression; programs; protein phosphatase 2A regulatory subunit 65 kDa; research study; stem cell biology; stem cell niche; stem cell population; trait; tumor; tumor growth; tumorigenesis; tumorigenic

Project Summary Abnormalities in intestinal stem cell programs underlie the pathogenesis of colorectal cancer (CRC), a disease that affected over 130,000 individuals in 2015. Therefore, further defining programs that regulate fundamental stem cell processes may lead to novel therapeutic targets. Accordingly, the Wnt signaling pathway plays a fundamental role in maintaining intestinal homeostasis and disruptions in this pathway are inextricably linked to the development of colon cancer. β-catenin is the key effector of Wnt signaling, transducing signals to the nucleus or acting as a component of the cadherin complex at the cell membrane. The preponderance of Wnt mutations in CRC ultimately increase levels of β-catenin within the cell. However, targeting this pathway has, as of yet, not yielded therapeutic efficacy. Blood vessel epicardial substance (BVES) is a tight junction-associated protein discovered in a cDNA screen of the developing heart. BVES is downregulated in CRC and overexpression of BVES impairs tumor growth, identifying a tumor suppressive role for BVES in carcinogenesis. BVES has also been shown to affect Wnt activity. BVES expression reduces Wnt reporter activity and in mouse models of inflammatory carcinogenesis, Bves-/- tumors have increased levels of β-catenin. As Wnt signaling is critical in maintenance of the intestinal stem cell niche, Bves-/- mice also have activated stem cell programs. Taken together, it is hypothesized that BVES modulates Wnt signaling, principally through an effect on β-catenin. This hypothesis will be tested via two focused, mechanistic, and hypothesis driven specific aims that will expand our understanding of how BVES regulates Wnt signaling. First, the mechanism by which BVES alters β-catenin levels will be determined. BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, and it is hypothesized that through this interaction BVES modulates β-catenin. Alternatively, as BVES can localize to the membrane, β-catenin activity may be controlled through membrane sequestration. Second, a BVES conditional knockout mouse model will be employed to determine if loss of BVES in intestinal stem cells and subsequent alterations in Wnt signaling affect intestinal crypt dynamics. Novel 3D enteroid cultures will be employed to expand these studies and further characterize the functional domain of BVES responsible for modulating Wnt dependent phenotypes. These studies will then be translated into human derived tumoroid cultures to determine if restoring BVES function can modulate tumor growth. Our proposed studies will define the role of BVES in Wnt signaling, intestinal stem cell biology, and colorectal cancer. Importantly, clarifying the role of BVES may elucidate novel mechanisms to target this pro-tumorigenic pathway.

项目总结