Dietary control of stem cells in physiology and cancer

生理学和癌症中干细胞的饮食控制

• 批准号: 10058815
• 负责人: Omer Yilmaz
• 金额: $ 40.95万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-23 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058815
• 关键词: APC gene; Aging; Agonist; Biological Assay; Biology; Cells; Cellular biology; Colon Carcinoma; Cues; Daughter; Development; Diet; Disease; Engineering; Enzymes; Epidemiology; Fatty Acids; Foundations; Genetic; Genetic Transcription; Heterogeneity; High Fat Diet; Incidence; Intestinal Intraepithelial Neoplasia; Intestinal Neoplasms; Intestines; LGR5 gene; Lesion; Link; Maintenance; Malignant Neoplasms; Mammals; Maps; Mediating; Metabolic; Mus; Natural regeneration; Obesity; Organoids; PPAR alpha; PPAR delta; Pathway interactions; Pharmacology; Physiology; Population; Process; Production; Regulator Genes; Rodent; Role; Signal Transduction; Testing; Therapeutic; Transplantation; Tumor Suppressor Genes; adult obesity; cell type; dietary control; experimental study; fatty acid oxidation; in vivo; intestinal epithelium; intestinal homeostasis; intestinal tumorigenesis; mouse model; premalignant; progenitor; programs; response; self-renewal; single cell mRNA sequencing; stem cell biology; stem cell function; stem cells; stemness; tissue regeneration; tumor; tumor initiation; tumorigenic

PROJECT SUMMARY Organismal diet has a profound impact on tissue regeneration, aging, and disease in mammals. However, the mechanisms through which diet perturbs stem and progenitor cell biology and leads to diseases such as cancer are poorly understood. With the rise of obesity in the US population—more than 1 in 3 adults are obese –understanding the relationship between diet, stem cell biology, and cancer incidence takes on great importance. Focused on the mammalian intestine, we find that a pro-obesity high fat diet (HFD) augments the number and niche-independent function of Lgr5+ stem cells. Mechanistically, our studies indicate that a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem cells (ISCs) and progenitors (non-stem cells), and pharmacologic activation of PPAR-d recapitulates the effects that a HFD has on these cells. Furthermore, like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoids in a PPAR-d dependent manner. Interestingly, both HFD- and agonist-activated PPAR-d signaling endow progenitors with the organoid-initiating capacity normally restricted to stem cells. In fact, agonist-enforced PPAR-d signaling permits these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These observations provide a possible pathway for diet through modulating PPAR-d activation to alter not only the function of intestinal stem and progenitor cells but also their capacity to initiate tumors. Many questions remain regarding the impact of a HFD on the intestine, such as the in vivo, cell type-specific roles of PPAR-d in this process, and the identity of progenitor subsets that emerge in this diet to drive tumor development. Also, although PPAR-d is a master transcriptional regulator of genes involved in fatty acid oxidation (FAO), it is unclear whether intestinal stem and progenitor cells or tumors that arise in a HFD rely on this PPAR-d-activated FAO metabolic program for their maintenance. Specifically, we will test the hypotheses that PPAR-d mediates the in vivo effects of a HFD in ISCs and progenitors in intestinal homeostasis and tumor initiation (Aim 1); that a subset of non-stem cell progenitors acquire stemness and tumorigenic potential in a HFD and with enforced PPAR-d signaling (Aim 2); that a HFD or enforced PPAR-d signaling render ISCs, progenitors, or established tumors metabolically reliant on fatty acid oxidation for their maintenance (Aim 3).

项目总结 有机饮食对哺乳动物的组织再生、衰老和疾病有着深远的影响。然而， 饮食扰乱干细胞和祖细胞生物学并导致以下疾病的机制 人们对癌症知之甚少。随着美国人口肥胖率的上升-超过三分之一的成年人患有肥胖症 -了解饮食、干细胞生物学和癌症发病率之间的关系具有重要意义 重要性。 专注于哺乳动物的肠道，我们发现，有利于肥胖的高脂肪饮食(HFD)增加了数量 以及Lgr5+干细胞的非生态位功能。从机制上讲，我们的研究表明，HFD会导致 肠干细胞(ISCs)和肠干细胞(ISCs)中PPAR-d的强健信号 前体细胞(非干细胞)和PPAR-d的药理激活概括了HFD的作用 在这些细胞上。此外，像HFD一样，用脂肪酸体外处理肠道器官培养物 HFD的成分在依赖PPAR-d的情况下增强这些有机化合物的自我更新潜力 举止。有趣的是，HFD和激动剂激活的PPAR-d信号都赋予祖细胞 类有机物的启动能力通常仅限于干细胞。事实上，激动剂强制的PPAR-d信号允许 这些前体细胞在失去肿瘤抑制因子APC后在体内形成肿瘤。这些观察结果提供了一个 饮食的可能途径是通过调节PPAR-d的激活来改变肠干的功能 和祖细胞，但也包括它们引发肿瘤的能力。关于经济衰退的影响，仍然存在许多问题 HFD在肠道中的作用，如在体内，PPAR-d在这一过程中的细胞类型特异性作用，以及 在这种饮食中出现的驱动肿瘤发展的祖细胞亚群。另外，尽管PPAR-d是主程序 脂肪酸氧化相关基因的转录调控(FAO)，目前尚不清楚肠干 而在HFD中出现的祖细胞或肿瘤依赖于PPAR-d激活的粮农组织代谢程序 他们的维修费。 具体地说，我们将测试PPAR-d在ISCs和Hfd中介导HFD体内效应的假设 祖细胞在肠道内稳态和肿瘤启动中的作用(目标1)；非干细胞祖细胞的一个亚群 通过增强的PPAR-d信号获得HFD的干性和致瘤潜力(目标2)；HFD 或强制的PPAR-d信号使ISCs、祖细胞或已建立的肿瘤代谢依赖于脂肪 用于维护的酸氧化(目标3)。

项目成果

Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-δ Pathway.

• DOI: 10.1158/1078-0432.ccr-16-0775
• 发表时间: 2016-12-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Beyaz S;Yilmaz ÖH
• 通讯作者: Yilmaz ÖH