The role of cholesterol biosynthesis in metastatic and recurrent endometrialcancer

胆固醇生物合成在转移性和复发性子宫内膜癌中的作用

基本信息

批准号：
10560609
负责人：
Jae-Wook Jeong
金额：
$ 54.09万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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：
2022-09-23 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560609
关键词：
Abdomen Ablation Acceleration Adjuvant Therapy Animal Model Cells Cholesterol Data Development Diagnosis Disease Distant Metastasis Endometrial Carcinoma Estrogens Exhibits FDA approved Gene Expression Gene Targeting Genes Genetically Engineered Mouse High Fat Diet Histologic Human Hysterectomy Knowledge Lung Malignant Female Reproductive System Neoplasm Mediator Metastatic/Recurrent Mitogens Molecular Profiling Mus Mutant Strains Mice Mutate Mutation Neoplasm Circulating Cells Neoplasm Metastasis Operative Surgical Procedures PTEN gene Pathway interactions Patients Preclinical Testing Primary Neoplasm Progesterone Prognosis Proto-Oncogene Proteins c-akt Recurrence Recurrent Malignant Neoplasm Recurrent tumor Resolution Role Signal Transduction Staging Survival Rate Testing Therapeutic Tumor Suppressor Genes Uterus Visualization Woman Work atorvastatin cancer cell cancer recurrence cholesterol biosynthesis experimental study high risk improved in vivo innovation mTOR inhibition mouse model novel novel therapeutics overexpression pre-clinical prevent transcriptome tumor tumor progression tumorigenic

项目摘要

Endometrial cancer is the most common gynecologic malignancy, with an estimated 66,570 new cases in 2021. Although early-stage and low grade endometrial cancer generally exhibits a favorable prognosis, metastatic and recurrent endometrial cancer is incurable with currently available standard therapies for most women. Therefore, there is an urgent obligation to explore the mechanism of tumor metastasis and recurrence to further elucidate the progression of endometrial cancer. We have developed a genetically engineered mouse model for metastatic and recurrent endometrial cancer that implicates coexistent Pten and Mig-6 mutations in endometrial cancer. Pten mutation is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. After hysterectomy at stage I of endometrial cancer in mutant mice with deficiency of Pten and Mig-6, the double mutant mice developed recurrence of endometrial cancer in the abdomen and lung. Our preliminary results show that the expression of genes related to cholesterol biosynthesis pathway was significantly increased in the mutant mice. Based upon these results, we hypothesize that MIG-6 suppresses metastasis and recurrence in endometrial cancer with PTEN mutation by inhibiting cholesterol biosynthesis. Our Specific Aims are directed at understanding: 1) the tumorigenic effects of MIG-6 loss in recurrence of endometrial cancer with PTEN mutation; 2) the molecular signature of primary tumor, circulating tumor cells, and recurrent tumor in the mutant mice; and 3) the ability of statins to prevent recurrence in endometrial cancer. There is strong innovation in the novelty of our hypotheses and cutting-edge technical approaches. In particular, we will employ the first preclinical animal model that closely resembles human endometrial cancer with distant metastasis and recurrence.

子宫内膜癌是最常见的妇科恶性肿瘤，预计 2021 年新发病例为 66,570 例。尽管早期和低级别子宫内膜癌通常表现出良好的预后，但转移性子宫内膜癌对于大多数女性来说，目前可用的标准疗法无法治愈复发性子宫内膜癌。因此，探索肿瘤转移和复发的机制迫在眉睫。进一步阐明子宫内膜癌的进展。我们开发了一种基因工程小鼠转移性和复发性子宫内膜癌模型，表明 Pten 和 Mig-6 突变共存子宫内膜癌。 Pten 突变不足以引起远处转移，但同时切除 Pten 的小鼠 Mig-6 和 Pten 发生远处转移。突变小鼠子宫内膜癌 I 期子宫切除术后缺乏Pten和Mig-6的双突变小鼠在体内出现子宫内膜癌复发腹部和肺部。我们的初步结果表明，与胆固醇相关的基因的表达突变小鼠的生物合成途径显着增加。根据这些结果，我们假设 MIG-6 通过 PTEN 抑制子宫内膜癌的转移和复发通过抑制胆固醇生物合成而发生突变。我们的具体目标旨在了解：1) MIG-6 缺失对 PTEN 突变子宫内膜癌复发的致瘤作用； 2）分子突变小鼠的原发肿瘤、循环肿瘤细胞和复发肿瘤的特征； 3) 的能力他汀类药物可预防子宫内膜癌复发。我们假设的新颖性具有很强的创新性和尖端的技术方法。特别是，我们将采用第一个临床前动物模型与人类子宫内膜癌非常相似，具有远处转移和复发。