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

• 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
• 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

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.

项目摘要 结直肠癌（CRC）仍然是美国与癌症相关死亡的第三大主要原因。虽然过度 所有发生率都在下降，年轻人口的发病率在过去一直在稳步增加 三十年。虽然西方饮食和久坐的生活方式是促进早期的环境因素 结直肠癌（EOCRC；如50岁的个体所定义），遗传研究也已实施 Wnt/ß-catenin信号通路是EOCRC的驱动力。腺瘤性息肉病（APC）的突变 基因是肿瘤抑制剂，并编码该途径的负调节蛋白，高度普遍 在赞助CRC中。这些突变驱动了由ß-catenin控制的致癌基因表达程序 转录共同调节器。在 EOCRC肿瘤样品，但尚不清楚失控的Wnt/ß-catenin信号在EOCRC中的作用。这 该提案的目标是阐明关键的下游Wnt/ß-catenin基因靶标，并确定新颖的Wnt- 驱动EOCRC的途径调节器。在AIM 1中，我们将使用RNA-Seq定义差异基因表达 患者匹配的结肠片段和肿瘤的签名。我们将专注于已知的下游目标基因 Wnt/ß-catenin信号传导和使用人源性瘤驱动Eocrc的作用。在AIM 2中，我们 将使用CRISPR/CAS9敲除屏幕来识别对Wnt/ß-catenin负调节的新型蛋白质 来自EOCRC患者的人类结肠器官培养物中的信号传导。这项工作将确定新颖的驱动力 EOCRC的局限性，以更好地理解疾病发病机理并揭示潜在的新途径 治疗干预。