Inter-relationship between microbiota diversity, obesity and race in endometrial cancer

项目总结 肥胖和胰岛素抵抗是与肥胖风险增加和预后恶化相关的因素 子宫内膜癌(EC)。非裔美国人(AA)妇女死于EC的死亡率高于白人 (CAU)女性，这可能部分是由于再生障碍性贫血与糖尿病相比，肥胖和糖尿病的发生率更高 CAU患者。鉴于肠道微生物群因种族不同而不同，并与潜在的生物学有关 无论是肥胖还是癌症，肠道和子宫中的细菌可能是导致种族和 欧共体的肥胖差距。我们知识中的一个重大差距是，恶性肿瘤的微生物区系 子宫此前并未被定性。我们假设EC微生物区系存在，但因肥胖而不同 和种族地位，在EC的发病机制中起作用。 在我们的LKB1fl/flp53fl/fl小鼠模型中，饮食诱导的肥胖促进了肿瘤的发生 进展，导致肿瘤大小加倍。代谢组图谱显示显著差异 肥胖小鼠和瘦小鼠的内皮细胞之间的关系，包括能量代谢增强和肠道功能增强- 肥胖小鼠的微生物组相关代谢物。糖尿病药物二甲双胍提高了治疗糖尿病的疗效 肥胖小鼠，通过逆转肥胖对肠道微生物和 能量代谢的上调。我们为这项拨款提案奠定基础的初步研究评估了微生物区系 在21例早期妇女子宫内膜样内皮细胞中发现细菌存在于子宫内膜异位症后子宫内。 更年期的女人。在AA和CAU女性的肿瘤中，EC微生物区系多样性更大。 肥胖妇女和瘦妇女的内皮细胞之间的微生物区系特征是不同的。二甲双胍的0期临床试验 肥胖的EC患者对二甲双胍(定义为肿瘤细胞增殖减少)有反应 对肠道微生物组相关代谢物的影响更大。因此，我们在两只小鼠身上所做的初步工作 女性支持肥胖、种族、微生物群和EC之间潜在的关键联系。 因此，使用我们临床相关的肥胖EC基因工程小鼠模型，我们将确定 在特定的目标1中，如果肥胖症和肥胖症患者的正常和恶性子宫内膜的微生物区系谱不同 绝经后去卵巢的瘦小鼠。同时，在具体目标2中，我们将扩大我们的试点研究和 评估绝经后AA和CAU妇女中非肥胖和肥胖妇女的ECs是否存在微生物区系差异 (n=160，每组40例)。将对小鼠和女性的内皮细胞进行代谢组学分析，以便 得出与肥胖和种族驱动的子宫微生物区系差异相关的相应功能。覆盖在 微生物区系和代谢组谱分析技术以及跨物种比较将有助于 发现肥胖和AA种族在EC中出现的不同细菌存在的机制。这将是 可能会导致微生物区系导向治疗和降低风险的策略，从而改善再生障碍性贫血的结果 EC患者，这是一个公共卫生目标，与NIH/NCI的使命一致。

PROJECT SUMMARY Obesity and insulin resistance are factors associated with increased risk for and worse outcomes from endometrial cancer (EC). African American (AA) women suffer a higher mortality from EC than Caucasian (CAU) women, and this may be in part due to greater rates of both obesity and diabetes among AA versus CAU patients. Given that the gut microbiome differs by race and has been implicated in the underlying biology of both obesity and cancer, bacteria in the gut and uterus may be logical contributing causes for the racial and obesity disparities seen for EC. A significant gap in our knowledge is that the microbiota of the malignant uterus has not been previously characterized. We hypothesize that the EC microbiota exists, differs by obesity and race status and contributes to the pathogenesis of EC. In our LKB1fl/flp53fl/fl mouse model of endometrioid EC, diet-induced obesity promoted tumor progression, resulting in a doubling of tumor size. Metabolomic profiling revealed significant differences between the ECs in obese versus lean mice, including enhanced energy metabolism and increased gut- microbiome associated metabolites in obese mice. The diabetes drug metformin had heightened efficacy in obese mice, via reversal of the detrimental effects that obesity had on both the gut microbiome and upregulation of energy metabolism. Our pilot study foundational for this grant proposal assessed the microbiota in 21 early stage endometrioid ECs of women and found that bacteria exist in the uterus of the post- menopausal woman. EC microbiota diversity was greater in the tumors of AA versus CAU women, and tumor microbiota profiles were distinct between ECs of obese and lean women. A phase 0 clinical trial of metformin in obese EC patients showed that response to metformin (defined as a decrease in tumor cell proliferation) aligned with greater impact on gut microbiome-associated metabolites. Thus, our preliminary work in both mice and women support a potential critical link between obesity, race, the microbiome and EC. Thus, using our clinically relevant genetically engineered mouse model of obese EC, we will determine in Specific Aim 1 if the microbiota profiles differ between the normal and malignant endometrium in obese and lean post-menopausal, ovariectomized mice. In parallel, in Specific Aim 2 we will expand on our pilot study and assess if the microbiota differ between ECs of non-obese and obese post-menopausal AA and CAU women (N=160 total, 40 per group). Metabolomic profiling will be performed on the ECs from mice and women so as to elicit corresponding function related to obesity- and race-driven differences in the uterine microbiota. Overlay in the techniques of microbiota and metabolomic profiling as well as cross-species comparisons will facilitate discovery of the mechanisms of differing bacterial presence that occur with obesity and AA race in EC. This will potentially lead to microbiota-directed therapies and risk-reducing strategies that will improve outcomes for AA EC patients, which is a public health goal that aligns with the mission of the NIH/NCI.