Nutritionally Driven Sporadic Intestinal Tumors: Impact on Stem Cells

营养驱动的散发性肠肿瘤：对干细胞的影响

基本信息

批准号：
10410368
负责人：
LEONARD H AUGENLICHT
金额：
$ 48.34万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-05 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410368
关键词：
APC mutation Accounting Adult Affect Alleles Back Biochemical Biogenesis Cancer Etiology Carbohydrates Cell Compartmentation Cell Lineage Cell Maturation Cell physiology Cells Citric Acid Cycle Colorectal Cancer Columnar Cell Complex Consumption DNA Damage DNA Repair DNA Sequence Alteration Data Developed Countries Development Diet Dietary Practices Disease Electron Transport Energy Metabolism Energy-Generating Resources Enzymes Epigenetic Process Epithelial Cells Evaluation Evolution Fatty acid glycerol esters Frequencies Genes Genetic Genetic Models High-Risk Cancer Histologic Homeostasis Human Incidence Intake Intervention Intestinal Mucosa Intestinal Neoplasms Intestines Knock-out LGR5 gene Large Intestine Link LoxP-flanked allele Metabolic Pathway Mismatch Repair Mitochondria Modeling Molecular Mucous Membrane Mus Mutation Mutation Spectra Nutrient Nutritional Oxidative Phosphorylation Pathway interactions Patients Population Prevention Probability Publications Publishing Relative Risks Reporting Risk Risk Factors Rodent Sentinel Small Intestines Somatic Cell Somatic Mutation Testing Time Tissues WNT Signaling Pathway Work adult stem cell base colorectal cancer risk conditional knockout dietary dietary control early detection biomarkers exome sequencing feeding genome-wide in vivo intestinal homeostasis intestinal tumorigenesis mouse genetics mouse model neoplastic cell novel strategies programs repaired response stem cell function stem cell population stem cells stem-like cell transcriptome sequencing tumor tumorigenesis western diet

项目摘要

Western-style diets are strongly linked to human sporadic colorectal cancer (CRC), the predominant subtype of all human CRCs. This can be recapitulated in the mouse fed a purified rodent diet (NWD1) mimicking intake of major human nutrient risk factors for CRC. Our extensive published work on this model has established that there are fundamental biochemical and molecular field effects in the histologically normal appearing mucosa of NWD1 fed mice, long before sporadic tumors develop. This includes altered epithelial cell maturation, expanded and elevated Wnt signaling throughout the mucosa, and altered energy metabolism. More recently, we reported that feeding NWD1 has profound effects on ability of Lgr5hi crypt base columnar cells to function as stem cells in intestinal homeostasis and in tumor development. Data submitted for publication (presented herein), establish that feeding NWD1 differentially programs Lgr5hi and Bmi1creERT2 marked intestinal stem cells (RNAseq analysis). In Lgr5hi cells, this significantly elevates expression of DNA damage response (DDR) genes, in particular in the mismatch repair pathway, suppresses accumulation of Lgr5hi cell somatic mutations, and alters mutational spectra and signature. Further, consistent with the shift we reported in relative utilization of carbohydrate and fat as energy sources in mice fed NWD1, there was reduced expression in Lgr5hi cells of genes encoding components of the TCA cycle and of multiple subunits for each of the 5 complexes of mitochondrial electron transport, and for Pgc1a, a master regulator of mitochondrial function and biogenesis. As a consequence, NWD1 reduced Lg5hi cell function in intestinal homeostasis and tumorigenesis, but increased ability of Bmi1 progeny to act as stem-like cells in homeostasis and tumor development. Therefore, NWD1 - highly relevant to human nutritional exposures strongly linked to population risk for CRC – had a major impact on sculpting the contribution of different intestinal stem cell populations to contribute to mucosal homeostasis and tumorigenesis. These dietary effects on adult stem cells are potentially paradigm shifting in terms of understanding risk for sporadic tumors. Our overall hypothesis is that these changes in long-lived stem cells provide new approaches for early evaluation and modulation of relative risk. Aim 1 identifies the evolution with time of epigenetic and genetic alterations by which NWD1 alters mouse intestinal/colonic adult stem cells in elevating probability for sporadic CRC, and the relative stability of such changes once established when the diet is altered. Aim 2 determines the impact of NWD1 on altered DNA damage response to promoting tumorigenesis from the different stem cell populations. Aim 3 determines the extent to which genetic inactivation of Pgc1a targeted to Lgr5 stem cells of the intestinal and colonic mucosa is sufficient to recapitulate the effects of NWD1 on alteration of Lgr5 stem cell programming and contribution of Lgr5 cells to intestinal homeostasis and tumorigenesis.

西式饮食与人类散发性结直肠癌（CRC）密切相关，CRC是主要的癌症所有人类 CRC 的亚型都可以在喂食纯化啮齿动物饮食的小鼠 (NWD1) 中重现。模仿人类结直肠癌主要营养风险因素的摄入量。模型已经证实，生物化学和分子场效应存在于早在散发性肿瘤发生之前，NWD1 喂养的小鼠的粘膜组织学表现就正常。包括上皮细胞成熟的改变、整个粘膜 Wnt 信号的扩展和升高，和能量代谢。最近，我们报道了 NWD1 的喂养对 Lgr5hi 隐窝碱基的能力具有深远的影响柱状细胞在肠道稳态和肿瘤发育中充当干细胞。提交出版（本文介绍），确定喂养 NWD1 差异程序 Lgr5hi 和 Bmi1creERT2 标记的肠道干细胞（RNAseq 分析）在 Lgr5hi 细胞中，这显着升高。 DNA损伤反应（DDR）基因的表达，特别是在错配修复途径中，抑制 Lgr5hi 细胞体细胞突变的积累，并改变突变谱和特征。此外，与我们报告的碳水化合物和脂肪作为能量的相对利用的变化一致在喂食 NWD1 的小鼠中，Lgr5hi 细胞中编码成分的基因表达减少 TCA 循环和线粒体电子传递 5 个复合物中每一个的多个亚基，对于 Pgc1a，线粒体功能和生物发生的主要调节因子，NWD1 也是如此。降低 Lg5hi 细胞在肠道稳态和肿瘤发生中的功能，但增加 Bmi1 的能力子代在高度稳态和肿瘤发展中充当干细胞样细胞。与人类营养暴露相关，与人群罹患结直肠癌的风险密切相关——具有重大影响塑造不同肠道干细胞群对粘膜的贡献这些饮食对成体干细胞的影响可能是范例。我们对散发性肿瘤风险的理解发生了转变。长寿干细胞的研究为早期评估和调节相对风险提供了新方法。目标 1 确定 NWD1 改变的表观遗传和遗传改变随时间的演变小鼠肠/结肠成体干细胞提高散发性结直肠癌的概率，以及相对一旦建立这种变化的稳定性，就决定了目标 2 改变饮食时的影响。 NWD1 改变 DNA 损伤反应以促进不同干细胞的肿瘤发生目标 3 确定针对 Lgr5 干的 Pgc1a 基因失活的程度。肠和结肠粘膜细胞足以重现 NWD1 对改变 Lgr5 干细胞编程以及 Lgr5 细胞对肠道稳态和肿瘤发生的贡献。