Wnt/beta-catenin signaling in early-onset colorectal cancer

早发性结直肠癌中的 Wnt/β-连环蛋白信号传导

基本信息

批准号：
10648233
负责人：
Gregory S. Yochum
金额：
$ 8.3万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-04 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648233
关键词：
APC gene APC mutation Address Adherence Attention Automobile Driving Biochemical Biological Assay Biological Models CRISPR/Cas technology Cancer Etiology Caring Cells Cessation of life Chromatin Colon Colonic Neoplasms Colonoscopy Colorectal Colorectal Cancer Colorectal Neoplasms Data Data Set Development Diagnosis Diagnostic Disease Environmental Risk Factor Epigenetic Process Familial Adenomatous Polyposis Syndrome Future Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Research Genetic Screening Genetic Transcription Genomics Goals Green Fluorescent Proteins Growth Growth Factor Human Incidence Individual Knock-out Knowledge Lead Lentivirus Malignant Neoplasms Modality Mutation Nuclear Oncogenic Operative Surgical Procedures Organoids Outcome Pathogenesis Pathway interactions Patient Care Patients Pattern Population Proteins Recommendation Research Research Personnel Resected Role Sampling Seminal Signal Pathway Signal Transduction Talents Testing Therapeutic Intervention Tissue-Specific Gene Expression Tissues Transcription Coactivator Tumor Suppressor Proteins Uncertainty Unhealthy Diet Western Blotting Work beta catenin biobank colon cancer patients colon carcinogenesis colon growth design differential expression early onset colorectal cancer early-onset colorectal carcinogenesis effective therapy fusion gene genetic analysis genetic regulatory protein genetic signature genome-wide improved lentivirally transduced novel novel marker novel therapeutics patient population programs screening sedentary lifestyle small hairpin RNA transcriptome sequencing tumor western diet

项目摘要

PROJECT SUMMARY Colorectal cancer (CRC) remains the third leading cause of cancer related deaths in the US. Although the over- all incidence is declining, the incidence in the younger population has been steadily increasing over the past thirty years. While a western diet and a sedentary lifestyle are among contributing environmental factors to early onset colorectal cancer (EOCRC; as defined in individuals <50 years old), genetic research has also implicated the Wnt/ß-catenin signaling pathway as a driver of EOCRC. Mutations in the adenomatous polyposis coli (APC) gene, which is a tumor suppressor and encodes a negative regulatory protein of the pathway, are highly prevalent in spontaneous CRC. These mutations drive an oncogenic gene expression program controlled by the ß-catenin transcriptional co-regulator. APC mutations, and other regulators of Wnt/ß-catenin signaling, are also found in EOCRC tumor samples, but the role of deregulated Wnt/ß-catenin signaling in EOCRC is not understood. The goals of this proposal are to elucidate critical downstream Wnt/ß-catenin gene targets and to identify novel Wnt- pathway modulators that drive EOCRC. In Aim 1, we will use RNA-seq to define differential gene expression signatures in patient-matched colonic segments and tumors. We will focus on known downstream target genes of Wnt/ß-catenin signaling and test their role(s) in driving EOCRC using human-derived tumoroids. In Aim 2, we will use a CRISPR/Cas9 knockout screen to identify novel proteins that negatively regulate Wnt/ß-catenin signaling in human colonic organoid cultures derived from EOCRC patients. This work will identify novel drivers of EOCRC which is needed to better understand disease pathogenesis and to reveal new avenues for potential therapeutic intervention.

项目概要结直肠癌 (CRC) 仍然是美国癌症相关死亡的第三大原因。所有发病率都在下降，年轻人口的发病率在过去一直在稳步上升三十年来，西方饮食和久坐的生活方式是导致早衰的环境因素之一。发病结直肠癌（EOCRC；定义为<50岁的个体），遗传研究也表明 Wnt/ß-连环蛋白信号通路作为 EOCRC 的突变驱动因素。基因是一种肿瘤抑制因子，编码该途径的负调节蛋白，非常普遍在自发性 CRC 中，这些突变驱动由 ß-连环蛋白控制的致癌基因表达程序。 APC 突变以及 Wnt/β-连环蛋白信号传导的其他调节因子也存在于 EOCRC 肿瘤样本，但失调的 Wnt/ß-连环蛋白信号在 EOCRC 中的作用尚不清楚。该提案的目标是阐明关键的下游 Wnt/ß-catenin 基因靶标并鉴定新的 Wnt- 驱动 EOCRC 的途径调节剂在目标 1 中，我们将使用 RNA-seq 来定义差异基因表达。我们将重点关注已知的下游靶基因。在目标 2 中，我们研究了 Wnt/ß-连环蛋白信号传导并测试它们在驱动 EOCRC 中的作用。将使用 CRISPR/Cas9 敲除筛选来鉴定负调节 Wnt/ß-catenin 的新型蛋白质这项工作将确定来自 EOCRC 患者的人类结肠类器官培养物中的信号传导。 EOCRC 需要更好地了解疾病发病机制并揭示潜在的新途径治疗干预。