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

项目摘要 肥胖和胰岛素抵抗是与下列因素相关的风险增加和更差的结果： 子宫内膜癌（EC）。非裔美国人（AA）女性患EC的死亡率高于高加索人 (CAU)女性，这可能部分是由于AA与AA相比， CAU患者。鉴于肠道微生物组因种族而异，并与潜在的生物学有关， 在肥胖和癌症中，肠道和子宫中的细菌可能是种族和性别的合理原因。 肥胖差异见于EC。我们知识中的一个重大空白是，恶性肿瘤的微生物群 子宫以前没有特征。我们假设EC微生物群存在， 和种族地位，并有助于EC的发病机制。 在我们的LKB 1fl/flp53 fl/fl类胡萝卜素EC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。代谢组学分析显示， 肥胖小鼠与瘦小鼠的内皮细胞之间的差异，包括增强的能量代谢和增加的肠道- 肥胖小鼠中的微生物组相关代谢物。糖尿病药物二甲双胍在治疗糖尿病方面 肥胖小鼠，通过逆转肥胖对肠道微生物组和 能量代谢的上调。我们的试点研究基础这项拨款建议评估了微生物群 对21例早期子宫内膜样癌患者进行了细菌学检查， 更年期妇女与CAU女性相比，AA女性的肿瘤EC微生物群多样性更大， 微生物群分布在肥胖和瘦女性的EC之间是不同的。二甲双胍的0期临床试验， 肥胖EC患者显示对二甲双胍的反应（定义为肿瘤细胞增殖减少） 与对肠道微生物组相关代谢物的更大影响一致。因此，我们在两种小鼠中的初步工作 女性支持肥胖、种族、微生物组和EC之间的潜在关键联系。 因此，使用我们的临床相关的肥胖EC基因工程小鼠模型，我们将确定 在特定目标1中，如果肥胖和肥胖患者的正常和恶性子宫内膜之间的微生物群谱不同， 瘦的绝经后卵巢切除小鼠。同时，在具体目标2中，我们将扩大我们的试点研究， 评估非肥胖和肥胖绝经后AA和CAU女性EC之间的微生物群是否不同 （共160例，每组40例）。将对来自小鼠和女性的EC进行代谢组学分析，以 引出与肥胖和种族驱动的子宫微生物群差异相关的相应功能。上的覆盖 微生物群和代谢组学分析以及跨物种比较技术将有助于 发现EC中肥胖和AA种族发生的不同细菌存在的机制。这将 可能导致微生物群导向的治疗和降低风险的策略，这将改善AA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.