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

• 批准号: 10630909
• 负责人: Robert Stephen Chapkin
• 金额: $ 53.69万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 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/10630909
• 关键词: APC gene; APC mutation; Abate; Address; Attenuated; Automobile Driving; Biochemical; Biological Models; Biophysics; Cell Line; Cell Shape; Cell membrane; Cell surface; Cells; Cholesterol; Cholesterol Homeostasis; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Development; Drosophila genus; Drug usage; Engineering; Face; Goals; Homeostasis; Human; Implant; Intestines; Link; Malignant Neoplasms; Membrane; Membrane Lipids; Membrane Microdomains; Midgut; Modeling; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Organoids; Phenotype; Plasma Cells; Prevention strategy; Proteolipids; Receptor Activation; Research; Risk Reduction; Role; Shapes; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Transgenic Organisms; Tumor Suppressor Genes; WNT Signaling Pathway; Work; antagonist; beta catenin; biophysical properties; cancer prevention; colonic crypt; colorectal cancer prevention; colorectal cancer risk; dietary; driving force; in vivo; mouse model; mutant; nanocluster; neoplastic cell; novel; novel strategies; overexpression; receptor; receptor expression; self-renewal; side effect; spatiotemporal; stem cells; targeted treatment; tumor; tumorigenesis

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。 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%) 不幸的是，由于以下原因，使用药物靶向异常 Wnt 信号传导的尝试仍然面临多重障碍。 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 了解其作用机制后，迫切需要进一步评估无毒作用。 因此，本提案寻求开发新型膜靶向治疗方法。 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 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，以解开基于膜的复杂性。 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 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 我们建议修改细胞膜以抑制异常的 Wnt 信号传导和结肠肿瘤的形成。 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。

项目成果

scTenifoldKnk: An efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation.

• DOI: 10.1016/j.patter.2022.100434
• 发表时间: 2022-03-11
• 期刊: PATTERNS
• 影响因子: 6.5
• 作者: Osorio, Daniel;Zhong, Yan;Li, Guanxun;Xu, Qian;Yang, Yongjian;Tian, Yanan;Chapkin, Robert S.;Huang, Jianhua Z.;Cai, James J.
• 通讯作者: Cai, James J.

Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation.

• DOI: 10.1016/j.jlr.2021.100026
• 发表时间: 2021
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Fuentes NR;Mlih M;Wang X;Webster G;Cortes-Acosta S;Salinas ML;Corbin IR;Karpac J;Chapkin RS
• 通讯作者: Chapkin RS

Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.

• DOI: 10.1038/s41467-023-39640-w
• 发表时间: 2023-07-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Erazo-Oliveras, Alfredo;Munoz-Vega, Monica;Mlih, Mohamed;Thiriveedi, Venkataramana;Salinas, Michael L.;Rivera-Rodriguez, Jaileen M.;Kim, Eunjoo;Wright, Rachel C.;Wang, Xiaoli;Landrock, Kerstin K.;Goldsby, Jennifer S.;Mullens, Destiny A.;Roper, Jatin;Karpac, Jason;Chapkin, Robert S.
• 通讯作者: Chapkin, Robert S.

Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer.

• DOI: 10.1038/s43856-023-00336-3
• 发表时间: 2023-08-09
• 期刊: COMMUNICATIONS MEDICINE
• 作者: Schmidt, Daniel R;Gramatikov, Iva Monique T;Sheen, Allison;Williams, Christopher L;Hurwitz, Martina;Dodge, Laura E;Holupka, Edward;Kiger, W S 3rd;Cornwall-Brady, Milton R;Huang, Wei;Mak, Howard H;Cormier, Kathleen S;Condon, Charlene;Dane Wittrup, K;Yilmaz, Omer H;Stevenson, Mary Ann;Down, Julian D;Floyd, Scott R;Roper, Jatin;Vander Heiden, Matthew G
• 通讯作者: Vander Heiden, Matthew G