Wnt signaling in obesity-associated colorectal cancer

肥胖相关结直肠癌中的 Wnt 信号传导

基本信息

批准号：
10445874
负责人：
Jatin Roper
金额：
$ 36.83万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-23 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445874
关键词：
APC gene Affect Agonist American Biological Assay Biotechnology Body mass index CRISPR screen CRISPR/Cas technology Cancer Model Cells Clinical Trials Colon Carcinoma Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Data Development Disease Family Genes Genetic Transcription Genetically Engineered Mouse Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases High Fat Diet In Vitro Incidence Intestinal Cancer Intestinal Neoplasms Intestines KRASG12D LGR5 gene Lead Maintenance Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Mus Nature Neoplasm Metastasis Nuclear Translocation Obesity Organoids PPAR alpha PPAR delta Patients Population Prevention strategy Protocols documentation Research Risk Factors Role Signal Transduction Testing Therapeutic Thinness Tissue Sample Transducers Transplantation Tumor Suppressor Genes WNT Signaling Pathway Weight base beta catenin cancer initiation cancer stem cell cancer type chromatin immunoprecipitation cohort colon cancer patients colon carcinogenesis colon tumorigenesis colorectal cancer metastasis colorectal cancer progression colorectal cancer treatment diet-induced obesity dietary control in vivo inhibitor innovation loss of function member mortality mortality risk mouse model novel obese person pre-clinical programs restoration rho rho GTP-Binding Proteins single cell analysis single-cell RNA sequencing stem cell expansion stem cell function stem cell proliferation stem cell self renewal stem cells therapeutic target transplant model treatment strategy tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary Obesity affects 42% of the U.S. population and is a major risk factor for the development of colorectal cancer. Obese colorectal cancer patients have a five-fold increased risk of death compared to normal weight counterparts. However, the mechanisms by which obesity increases colorectal cancer progression and metastasis are poorly understood, which limits the development of effective prevention and treatment strategies for colorectal cancer in obese individuals. The vast majority of colorectal cancers are initiated by loss of the tumor suppressor gene Apc in colonic stem cells, and subsequent activation of the Wnt signaling pathway. Wnt signaling is also required for maintenance of advanced colorectal cancers and metastases. Research from our group demonstrates that diet-induced obesity markedly upregulates Wnt signaling in intestinal and colonic stem cells by promoting a peroxisome proliferator-activated receptor delta (PPAR-d) transcriptional program, which in turn increases cancer development. These findings suggest that inhibition of Wnt signaling is a highly attractive therapeutic strategy for obesity-associated colorectal cancer. We and others have demonstrated that colon tumors are maintained by Lgr5+ cancer stem cells, and single cell RNA sequencing data from our lab shows that these cells are Wnt-active, while non-cancer stem cells are Wnt-low. However, development of Wnt inhibitors to treat Apc-deficient cancers or to target cancer stem cells has proven elusive. Rac1-GTP, a member of the Rho family of GTPases, is an intracellular transducer that promotes Wnt signaling by mediating nuclear translocation of beta-catenin. Prex1 is a Rac-specific Rho GTPase guanine nucleotide exchange factor that activates Rac1 by facilitating the exchange of GTP to GTP. We found that Prex1 and active Rac1-GTP are highly enriched in intestines and colon cancers of mice treated with high fat diet or an agonist of PPAR-d. Loss of Rac1 signaling markedly reduces intestinal tumor initiation by inhibiting Wnt activation. Our long-term goal is to understand mechanisms of Wnt activation in colorectal cancer and to develop new treatment strategies for this disease. Here, we hypothesize that Prex1-dependent Rac1-GTP activity mediates obesity-induced tumorigenesis by inducing Wnt signaling in Lgr5+ cancer stem cells. In Aim 1, we will determine the role of Prex1 signaling in high fat diet and PPAR-d-mediated intestinal stem cell regeneration and tumor initiation. In Aim 2, we will determine the function of the Prex1 / Rac1-GTP signaling axis in high fat diet and PPAR-d-dependent colorectal cancer stem cell function. In Aim 3, we will identify the role of PPAR-d transcriptional targets in colorectal cancer stem cell function in the setting of diet- induced obesity. The goal of this proposal is to identify mechanisms by which obesity-induced Wnt signaling promotes colorectal cancer progression. Our studies will provide preclinical rationale for clinical trials to test Rac1-GTP inhibitors for the treatment of colorectal cancer, particularly in obese individuals, by inhibiting Wnt signaling.

项目概要肥胖影响着 42% 的美国人口，是结直肠癌发生的主要危险因素。与正常体重相比，肥胖结直肠癌患者的死亡风险增加五倍同行。然而，肥胖加速结直肠癌进展的机制和对转移知之甚少，限制了有效预防和治疗的发展肥胖个体结直肠癌的治疗策略。绝大多数结直肠癌是由丢失引起的结肠干细胞中抑癌基因 Apc 的表达，以及随后 Wnt 信号传导的激活途径。 Wnt 信号传导对于晚期结直肠癌和转移的维持也是必需的。我们小组的研究表明，饮食引起的肥胖显着上调 Wnt 信号传导通过促进过氧化物酶体增殖物激活受体 δ (PPAR-d) 促进肠道和结肠干细胞转录程序，进而增加癌症的发展。这些发现表明，抑制 Wnt 信号传导对于肥胖相关结直肠癌来说是一种极具吸引力的治疗策略。我们和其他人已经证明结肠肿瘤是由 Lgr5+ 癌症干细胞和单细胞 RNA 维持的我们实验室的测序数据显示这些细胞具有 Wnt 活性，而非癌症干细胞的 Wnt 水平较低。然而，用于治疗 Apc 缺陷型癌症或靶向癌症干细胞的 Wnt 抑制剂的开发已取得进展。事实证明难以捉摸。 Rac1-GTP 是 GTPases Rho 家族的成员，是一种细胞内转导器，通过介导 β-catenin 的核转位促进 Wnt 信号传导。 Prex1 是 Rac 特定的 Rho GTPase 鸟嘌呤核苷酸交换因子，通过促进 GTP 交换为 GTP 来激活 Rac1。我们发现 Prex1 和活性 Rac1-GTP 在接受治疗的小鼠的肠癌和结肠癌中高度富集高脂肪饮食或 PPAR-d 激动剂。 Rac1 信号传导的缺失可显着减少肠道肿瘤的发生通过抑制 Wnt 激活。我们的长期目标是了解结直肠中 Wnt 激活的机制癌症并为这种疾病开发新的治疗策略。在这里，我们假设 Prex1 依赖 Rac1-GTP 活性通过在 Lgr5+ 癌症干细胞中诱导 Wnt 信号传导介导肥胖诱导的肿瘤发生细胞。在目标 1 中，我们将确定 Prex1 信号在高脂肪饮食和 PPAR-d 介导的肠道中的作用干细胞再生和肿瘤起始。在目标 2 中，我们将确定 Prex1 / Rac1-GTP 的功能高脂肪饮食中的信号轴和 PPAR-d 依赖性结直肠癌干细胞功能。在目标 3 中，我们将确定 PPAR-d 转录靶标在饮食设置中结直肠癌干细胞功能中的作用诱发肥胖。该提案的目标是确定肥胖诱导 Wnt 信号传导的机制促进结直肠癌的进展。我们的研究将为临床试验提供临床前理论依据 Rac1-GTP 抑制剂通过抑制 Wnt 来治疗结直肠癌，特别是肥胖个体发信号。