The role of cholesterol biosynthesis in metastatic and recurrent endometrial cancer

胆固醇生物合成在转移性和复发性子宫内膜癌中的作用

• 批准号: 10467152
• 负责人: Jae-Wook Jeong
• 金额: $ 25.49万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467152
• 关键词: Abdomen; Ablation; Adjuvant; Animal Model; Cells; Cholesterol; Data; Development; Diagnosis; 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 of activation protein; 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 tumor; Resolution; Role; Signal Transduction; Staging; Testing; Therapeutic; Tumor Suppressor Genes; Uterus; Woman; Work; atorvastatin; base; 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

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，2021年估计有66,570例新病例。 尽管早期和低级别的子宫内膜癌通常表现出良好的预后， 而对于大多数女性来说，目前可用的标准疗法是无法治愈复发的子宫内膜癌的。 因此，探讨肿瘤转移复发的机制迫在眉睫。 进一步阐明子宫内膜癌的进展。我们已经开发出一种基因工程小鼠 Pten和Mig-6基因突变共存的子宫内膜癌转移和复发模型 子宫内膜癌。PTEN突变不足以导致远处转移，但同时消融的小鼠 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 在缺乏Pten和Mig-6的情况下，双突变小鼠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表达 突变小鼠的生物合成途径显著增加。基于这些结果，我们 假设MIG-6抑制PTEN治疗子宫内膜癌的转移和复发 通过抑制胆固醇的生物合成而发生突变。我们的具体目标是了解：1) MIG-6缺失在PTEN突变子宫内膜癌复发中的致瘤作用 突变小鼠的原发肿瘤、循环肿瘤细胞和复发肿瘤的特征；以及3) 他汀类药物预防子宫内膜癌复发。我们假设的新颖性有很强的创新性 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 与人类子宫内膜癌相似，有远处转移和复发。