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Elucidating a novel WNT4 regulatory axis as a driver of gynecologic cancer health disparities

阐明新的 WNT4 调节轴作为妇科癌症健康差异的驱动因素

基本信息

批准号：
10773991
负责人：
Benjamin G Bitler
金额：
$ 64.56万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2023-09-21 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10773991
关键词：
ARID1A gene Address Adjuvant Chemotherapy Affect African Asian Asian population Attenuated Automobile Driving Binding Sites Biology CRISPR/Cas technology California Canada Cancer Cell Growth Cancer Etiology Cancer Model Cancer Patient Cancer cell line Caucasians Cell Line Cell Respiration Cell Survival Cell Therapy Chemoresistance Cisplatin Clear cell carcinoma Clinical Clustered Regularly Interspaced Short Palindromic Repeats Colorado Data Dependence Disease Disparity East Asian Ethnic Origin Ethnic Population Etiology Female Genital Neoplasms Foundations Frequencies Gene Frequency Genes Genetic Genetic Polymorphism Genotype Goals Growth Gynecologic Gynecologic Pathology Human In Vitro Incidence Knock-in Knock-in Mouse Latinx Latinx population Ligands Link Malignant Epithelial Cell Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Metabolic Metabolism Mitochondria Modeling Mus Neoadjuvant Therapy Nuclear Receptors Organogenesis Outcome Ovarian Ovarian Clear Cell Tumor Patient-Focused Outcomes Patients Phenotype Population Precision therapeutics Protein Array Protein Array Analysis Regulation Resistance Risk Risk Assessment Risk Factors Role Signal Transduction Single Nucleotide Polymorphism Site Small Interfering RNA Specimen Tissues Tumor Tissue Variant WNT4 gene Woman Work cancer cell cancer health disparity cancer risk cancer subtypes chemotherapy cohort defined contribution disorder risk genetic risk factor genetic variant genome-wide glucose metabolism human data improved in vivo knock-down lipid metabolism metabolomics novel novel therapeutics outcome disparities overexpression patient subsets population based programs protein metabolism therapy resistant transcription factor treatment response tumor tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Gynecologic malignancies such as ovarian cancer (OvCa) are among the deadliest cancers affecting women due to therapy resistance and limited understanding of disease etiology and risk. An under-explored risk factor is Wnt ligand WNT4, which is central to ovarian organogenesis. Over 20 studies link WNT4 polymorphisms with increased risk for gynecologic pathologies; one polymorphism at a key WNT4 regulatory site (rs3820282) is associated with 10-25% increased risk for OvCa, but the mechanism(s) is unknown. Our work links WNT4 to cancer cell growth, metabolism, and therapy resistance. We find WNT4 over-expression is sufficient to mediate chemotherapy resistance in vitro, and resistance with increased metastatic outgrowth in vivo, and that WNT4 expression is strongly induced in OvCa cells surviving neoadjuvant chemotherapy. Importantly, the rs3820282 variant allele in the WNT4 regulatory site creates a binding site for nuclear receptor-class transcription factors. CRISPR knock-in of the rs3820282 variant in mice increases Wnt4 expression in gynecologic tissues. Accordingly, in a protein array study of more than 100 OvCa tumor tissues, we found that AMPK activation and downstream signaling were increased in variant allele tumors. Conversely, glucose metabolism proteins were increased in wild-type tumors and inversely correlated with AMPK signaling, suggesting WNT4 genotype underpins metabolic remodeling. These observations suggest that the rs3820282 variant activates WNT4 to drive cancer phenotypes. However, the rs3820282 variant allele frequency (VAF) is widely divergent across ethnic populations, occurring at ~0% in African populations, ~15% in Caucasians, 20-40% in Latinx populations, and 45-55% in Asian populations, paralleling high incidence of aggressive, treatment-resistance OvCa subtype clear cell carcinoma (CCC) in Asian populations. Our goal is to determine how rs3820282 mediates disparities in ovarian cancer outcomes, mechanistically define genotype-driven tumor etiology, and identify therapies to exploit dependence on WNT4. Toward this goal, we will: 1) define how the rs3820282 variant activates WNT4-dependent metabolic remodeling; 2) define rs3820282-driven tumorigenesis and therapeutic response in a model of ovarian clear cell carcinoma (CCC); 3) determine how rs3820282 genotype impacts outcomes for patients with OvCa. With a foundation of rigorous supporting data from human specimens, we will undertake highly mechanistic studies to define the contribution of this common polymorphism to a cancer disparity, tumor metabolic reprogramming, gynecologic tumorigenesis, treatment response, and patient outcomes. We will leverage cutting-edge global metabolomics, tumorigenesis modeling, and human survival studies. Our approach can define the genotype-to-phenotype link, determine how this SNP drives OvCa cancer disparities, and identify approaches to exploit the underlying biology.

项目总结/摘要妇科恶性肿瘤，如卵巢癌（OvCa）是影响妇女的最致命的癌症之一这是由于治疗抗性和对疾病病因和风险的有限理解。一个未被充分研究的风险因素是Wnt配体WNT 4，其在卵巢器官发生中起中心作用。超过20项研究将WNT 4多态性妇科疾病风险增加; WNT 4关键调控位点的一个多态性（rs3820282）与OvCa风险增加10-25%相关，但机制尚不清楚。我们的工作将WNT 4与癌细胞生长、代谢和治疗抗性。我们发现WNT 4的过度表达足以介导体外化疗耐药性和体内转移性生长增加的耐药性，以及WNT 4 在新辅助化疗存活的OvCa细胞中强烈诱导表达。重要的是，rs3820282 WNT 4调节位点中的变体等位基因产生核受体类转录因子的结合位点。小鼠中rs3820282变体的CRISPR敲入增加了妇科组织中的Wnt 4表达。因此，在超过100个OvCa肿瘤组织的蛋白质阵列研究中，我们发现AMPK活化和下游信号传导在变体等位基因肿瘤中增加。相反，葡萄糖代谢蛋白质是在野生型肿瘤中增加，并与AMPK信号负相关，表明WNT 4基因型是代谢重塑的基础这些观察结果表明rs3820282变体激活WNT 4，驱动癌症表型。然而，rs3820282变异等位基因频率（VAF）在不同人群中差异很大。种族人群，在非洲人群中约占0%，在高加索人群中约占15%，在拉丁美洲人群中占20-40% 在亚洲人群中为45-55%，与侵袭性、耐药亚洲人群中的OvCa亚型透明细胞癌（CCC）。我们的目标是确定rs3820282 介导卵巢癌结局的差异，机械地定义基因型驱动的肿瘤病因，确定利用对WNT 4依赖性的疗法。为了实现这一目标，我们将：1）定义rs3820282 变体激活WNT 4依赖性代谢重塑; 2）定义rs3820282驱动的肿瘤发生，卵巢透明细胞癌（CCC）模型中的治疗反应; 3）确定rs3820282基因型影响OvCa患者的结局。在严格的人类支持数据的基础上，标本，我们将进行高度机械的研究，以确定这种共同的贡献，多态性与癌症差异，肿瘤代谢重编程，妇科肿瘤发生，治疗反应和患者结果。我们将利用最先进的全球代谢组学，肿瘤发生建模，和人类生存研究。我们的方法可以定义基因型与表型之间的联系，确定这种SNP 驱动OvCa癌症差异，并确定利用潜在生物学的方法。