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).

项目摘要 有机饮食对哺乳动物的组织再生，衰老和疾病有深远的影响。但是， 饮食植物茎和祖细胞生物学的机制，导致疾病，例如 癌症知之甚少。随着美国人口中肥胖的兴起 - 肥胖是肥胖的三分之一以上 - 了解饮食，干细胞生物学和癌症事件之间的关系很大 重要性。 专注于哺乳动物的肠道，我们发现亲肥胖高脂饮食（HFD）增加了数量 LGR5+干细胞的无裂非依赖性功能。从机械上讲，我们的研究表明HFD诱导A 肠道干细胞（ISC）和 祖细胞（非茎细胞）和PPAR-D的药物激活概括了HFD具有的影响 在这些细胞上。此外，像HFD一样，用脂肪酸对肠癌培养物进行了体内处理 构成HFD在PPAR-D依赖性中增强了这些器官的自我更新潜力 方式。有趣的是，HFD和激动剂激活的PPAR-D信号传导赋予了祖先 器官发射能力通常仅限于干细胞。实际上，激动剂强化的PPAR-D信号传导允许 这些祖细胞在失去肿瘤抑制APC后形成体内肿瘤。这些观察结果提供了 通过调节PPAR-D激活不仅改变肠茎的功能，饮食的可能途径 和祖细胞，也可以启动肿瘤的能力。关于某人的影响仍然存在许多问题 肠道上的HFD，例如PPAR-D在此过程中的体内，细胞类型特异性作用，以及的身份 在这种饮食中出现以促进肿瘤发育的祖细胞集。另外，尽管PPAR-D是大师 参与脂肪酸氧化（FAO）的基因的转录调节因子，尚不清楚肠干是否存在 HFD中出现的祖细胞或肿瘤依赖于此PPAR-D激活的粮农组织代谢程序 他们的维护。 具体而言，我们将测试PPAR-D介导HFD在ISC和ISC和 肠内稳态和肿瘤启动的祖细胞（AIM 1）；那个非茎细胞祖细胞的子集 在HFD中获取干性和致瘤潜力，并具有强制性的PPAR-D信号传导（AIM 2）；那个HFD 或强制执行PPAR-D信号传导ISC，祖细胞或已建立的肿瘤代谢依赖于脂肪 酸氧化以维持其维护（AIM 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