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Targeting plasma membrane spatial dynamics to suppress aberrant Wnt signaling

靶向质膜空间动力学抑制异常的 Wnt 信号传导

基本信息

批准号：
10047029
负责人：
Robert Stephen Chapkin
金额：
$ 57.92万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-03 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10047029
关键词：
Abate Address Adenomatous Polyposis Coli Attenuated Automobile Driving Biochemical Biological Models Biophysics Cell Line Cell membrane Cell surface Cells Cholesterol Cholesterol Homeostasis Clustered Regularly Interspaced Short Palindromic Repeats Colon Colon Carcinoma Colorectal Cancer Data Development Diet Drosophila genus Drug usage Engineering Face Goals Homeostasis Human Implant Intestines Lead Link Malignant Neoplasms Membrane Membrane Lipids Membrane Microdomains Midgut Modeling Mus Mutate Mutation Neoplasms Oncogenes Oncogenic Organoids Phenotype Plasma Cells Prevention strategy Proteolipids Receptor Activation Research Risk Role Signal Pathway Signal Transduction Testing Therapeutic Tissues Toxicology Transgenic Organisms Tumor Suppressor Genes Tumor Suppressor Proteins WNT Signaling Pathway Work base beta catenin biophysical properties cancer prevention colonic crypt colorectal cancer prevention colorectal cancer risk driving force in vivo mouse model mutant nano nanocluster neoplastic cell novel novel strategies overexpression receptor self-renewal side effect spatiotemporal stem cells targeted treatment tumor tumorigenesis

项目摘要

SUMMARY Dysregulation of the Wnt signaling pathway has been linked to cancer in multiple tissues. For example, most colorectal cancer (CRC) cases (~90%) are associated with aberrant Wnt signaling, due in part to mutations (>80%) associated with Adenomatous polyposis coli (APC), a multi-functional tumor suppressor gene. Unfortunately, attempts to target aberrant Wnt signaling using drugs still face multiple hurdles due to poor tumor cell targeting, negative side effects associated with required long-term treatments and a poor understanding of the mechanisms of action. Consequently, there is an urgent need to further assess non-toxic Wnt targeted therapeutic approaches. Therefore, this proposal seeks to develop novel membrane targeted therapeutic approaches to abate abnormal Wnt signaling in the colon. The scientific premise that supports the proposed research on Wnt receptor plasma membrane spatial dynamics is based on the fact that Wnt receptors and their signaling are required for CRC development within the context of a mutant APC background. This goal is supported by our novel discovery indicating that APC mutations causing abnormal Wnt signaling are associated with biophysical distortions in the cell plasma membrane, thereby promoting Wnt receptor nanoclustering and downstream signaling. We have also demonstrated that select membrane targeted dietary bioactives (MTDBs) can restore normal plasma membrane signaling by correcting cancer- causing biophysical distortions in the cell surface. In order to unravel the intricacies of membrane-based cancer prevention strategies, we propose to use novel mouse, Drosophila (fruit fly) and human colon organoid model systems to elucidate the underlying mechanisms by which MTDBs reshape the cell plasma membrane to suppress aberrant Wnt signaling. In Aim 1, we will further probe how mutated (oncogenic) APC perturbs cholesterol homeostasis in the colonic crypt, thereby increasing plasma membrane order and lipid raft-dependent spatiotemporal dynamics. In Aim 2, we will test our hypothesis that oncogenic APC-induced changes in cholesterol homeostasis alters the spatiotemporal organization (nanoclustering) of Wnt signaling-associated receptors, thereby promoting aberrant signaling. Aim 3 will examine the ability of MTDBs to attenuate aberrant Wnt signaling and colonic neoplasia phenotypes associated with oncogenic APC in part by “normalizing” plasma membrane biophysical properties. Upon completion of our proposed work, we expect to elucidate precisely how MTDBs therapeutically modify the cell membrane to suppress aberrant Wnt signaling and tumor formation in the colon. We propose that our novel approach to reshape plasma membrane Wnt receptor nanoclusters is a feasible CRC prevention or therapeutic strategy.

概括 Wnt 信号通路的失调与多种组织中的癌症有关。例如，大多数结直肠癌 (CRC) 病例 (~90%) 与异常的 Wnt 信号传导有关，部分原因是与腺瘤性息肉病大肠杆菌 (APC)（一种多功能肿瘤抑制因子）相关的突变 (>80%) 基因。不幸的是，使用药物靶向异常 Wnt 信号传导的尝试仍然面临多重障碍，因为肿瘤细胞靶向性差、与所需长期治疗相关的负面副作用以及较差的治疗效果了解作用机制。因此，迫切需要进一步评估无毒 Wnt 靶向治疗方法。因此，本提案旨在开发新型膜靶向减少结肠中异常 Wnt 信号传导的治疗方法。支持的科学前提所提出的 Wnt 受体质膜空间动力学研究基于以下事实：Wnt 在突变 APC 的背景下，受体及其信号传导是 CRC 发展所必需的背景。我们的新发现支持了这一目标，表明 APC 突变会导致异常 Wnt 信号传导与细胞质膜的生物物理扭曲相关，从而促进 Wnt 受体纳米簇和下游信号传导。我们还证明了选择膜靶向膳食生物活性物质（MTDB）可以通过纠正癌症来恢复正常的质膜信号传导导致细胞表面的生物物理扭曲。为了解开膜基的复杂性癌症预防策略，我们建议使用新型小鼠、果蝇（果蝇）和人类结肠类器官模型系统阐明 MTDB 重塑细胞质膜的潜在机制抑制异常的 Wnt 信号传导。在目标 1 中，我们将进一步探讨突变（致癌）APC 如何扰乱胆固醇稳态结肠隐窝，从而增加质膜秩序和脂筏依赖性时空动力学。在目标 2 中，我们将检验我们的假设，即致癌 APC 诱导的胆固醇稳态变化会改变 Wnt 信号相关受体的时空组织（纳米簇），从而促进异常信号。目标 3 将检查 MTDB 减弱异常 Wnt 信号传导和结肠的能力肿瘤表型与致癌 APC 相关，部分通过“正常化”质膜生物物理特性。完成我们提议的工作后，我们希望准确阐明 MTDB 如何进行治疗修饰细胞膜以抑制异常的 Wnt 信号传导和结肠中的肿瘤形成。我们建议我们重塑质膜 Wnt 受体纳米簇的新方法是一种可行的 CRC 预防方法或治疗策略。