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.

项目摘要肥胖症影响美国人群的42％，是结直肠癌发展的主要危险因素。肥胖的结直肠癌患者与正常体重相比，死亡风险增加了五倍同行。但是，肥胖增加结直肠癌进展的机制和转移的理解很少，这限制了有效的预防和治疗的发展肥胖个体结直肠癌的策略。绝大多数结直肠癌是通过损失引发的结肠干细胞中肿瘤抑制基因APC，然后激活Wnt信号路径。维持高级结直肠癌和转移酶也需要WNT信号传导。我们小组的研究表明，饮食引起的肥胖症明显上调Wnt信号传导肠道和结肠干细胞通过促进过氧化物酶体增殖物激活的受体三角洲（PPAR-D）转录计划，进而增加癌症的发展。这些发现表明抑制 Wnt信号传导是肥胖相关结直肠癌的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通过LGR5+癌症干细胞和单细胞RNA维持的来自我们实验室的测序数据表明这些细胞具有WNT活性，而非癌干细胞则是Wnt-low。但是，开发Wnt抑制剂以治疗APC缺陷癌或靶向癌症干细胞被证明难以捉摸。 Rac1-GTP是Rho GTPases家族的成员，是一种细胞内传感器，通过介导β-catenin的核易位来促进Wnt信号传导。 prex1是一个特异性的RHO GTPase鸟嘌呤核苷酸交换因子通过促进GTP与GTP的交换来激活Rac1。我们发现，Prex1和Active Rac1-GTP高度富含所治疗的小鼠的肠癌和结肠癌高脂饮食或PPAR-D的激动剂。 Rac1信号的丧失明显减少了肠道肿瘤的启动通过抑制Wnt激活。我们的长期目标是了解大肠激活的机制癌症并为这种疾病制定新的治疗策略。在这里，我们假设Prex1依赖性 Rac1-GTP活性通过在LGR5+癌症茎中诱导Wnt信号传导介导肥胖引起的肿瘤发生细胞。在AIM 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AIM 2中，我们将确定Prex1 / Rac1-GTP的功能高脂饮食中的信号轴和PPAR-D依赖性的结直肠癌干细胞功能。在AIM 3中，我们将在饮食中确定PPAR-D转录靶标在结直肠癌干细胞功能中的作用 - 诱发肥胖。该建议的目的是确定肥胖引起的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原理以进行测试 RAC1-GTP抑制剂治疗结直肠癌，特别是在肥胖个体中，通过抑制Wnt 信号。