Adipose tissue-colorectal tumor cross-talk: new targets for breaking the obesity-cancer link

脂肪组织-结直肠肿瘤串扰：打破肥胖与癌症联系的新目标

基本信息

批准号：
10493126
负责人：
Stephen D Hursting
金额：
$ 62.14万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10493126
关键词：
Address Adipocytes Adipose tissue African American Azoxymethane Biochemical Biological Biological Markers Biological Models Body mass index CRISPR screen Cancer Burden Cancer Etiology Cancer Model Candidate Disease Gene Caucasians Cessation of life Clinical Clinical Research Coculture Techniques Cohort Studies Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Complement Data Development Epidemiology Epithelial Epithelial Cells Etiology Experimental Models Fatty acid glycerol esters Fibrosis Gene Expression Genes Goals Human Hypertrophy In Vitro Inflammation Inflammatory Intercept Lead Light Link Lipomatous neoplasm Malignant Neoplasms Measures Mediating Metabolic Modeling Molecular Target Mus Obese Mice Obesity Obesity Epidemic Organoids Pathway interactions Patients Persons Population Pre-Clinical Model Prevention approach Prevention strategy Proteins Public Health Race Rectal Cancer Research Research Design Resources Risk Factors Role Serum Sex Differences Signal Transduction Testing Thinness Tissue Sample Tissues Translations Tumor Tissue United States Validation Visceral WNT Signaling Pathway base biomarker panel cancer type carcinogenesis clinical application clinically relevant cohort colon cancer patients colon cancer progression colon cancer risk colon tumorigenesis cost effective cytokine diet-induced obesity epidemiology study epithelial to mesenchymal transition experimental study in vitro Model in vivo in vivo Model innovation interdisciplinary collaboration metabolic profile metabolomics metastatic colorectal mouse model neoplastic cell novel novel strategies organoid transplantation overexpression pandemic disease pre-clinical preclinical study prospective response synergism transcriptome sequencing transcriptomics transplant model tumor

项目摘要

SUMMARY The pandemic rise of obesity worldwide is alarming, with the highest increases occurring in the United States. Obesity is a major risk factor for many cancer types, including colon cancer (CC). To date, the biologic mechanisms underlying this relationship, specifically the potential signaling between dysregulated adipose tissue and adjacent tumor, are incompletely understood. Given the rising rates of obesity and the challenges for many people to lose excess adipose tissue, an integrated, multilevel approach to efficiently identify crosstalk and validate key molecular targets is needed to develop effective mechanism-based strategies for prevention and control of obesity-driven CC. We hypothesize that the metabolic and inflammatory perturbations induced by obesity increase CC risk through altered signaling between adipocytes and colon epithelial/tumor cells, and that inhibition of this crosstalk will disrupt the obesity-CC link. We will test this hypothesis through the integration of: 1) a unique, prospective, multicenter epidemiologic cohort of normoweight to obese CC patients, from whom paired serum, tumor, and tumor-adjacent adipose tissue samples will be used to discover and validate lead targets; and 2) complementary in vivo models of lean and diet-induced obese mice with CC, together with in vitro/in vivo organoid models in which potential targets underlying the effects of obesity on CC will be tested mechanistically. This unique transdisciplinary approach utilizes innovative clinical/epidemiological and preclinical studies of biochemical, transcriptomic, and metabolomics analyses in rigorous study designs to identify and validate new targets for disrupting the reciprocal crosstalk between adipocytes and colonic epithelial cells. We propose three synergistic aims: 1a) to discover and validate targets underlying the adipose tissue-CC link, using 400 CC patients; b) to identify and validate metabolic and transcriptomic signatures of adipocyte-colonocyte crosstalk; 2) to characterize the adipocyte-colonocyte crosstalk underlying the obesity-CC link, using two rigorous mouse models of CC; 3) to determine the causal role of candidate epithelial target genes in obesity-associated CC progression using murine in vitro and in vivo organoid CC models. This paradigm-shifting transdisciplinary collaboration builds on extensive preliminary data and generates maximum synergy through complementary human and murine studies, using identical state-of-the-art biomarker panels and platforms across clinical and preclinical studies. We anticipate that findings from these proposed studies will address the clinical challenges associated with obesity and CC by establishing causal links of the most promising targets for intercepting and disrupting adipocyte-epithelial cell crosstalk.

概括全世界肥胖的大流行崛起令人震惊，在美国发生的最高增长。肥胖是许多癌症类型的主要危险因素，包括结肠癌（CC）。迄今为止，生物学这种关系背后的机制，特别是脂肪失调之间的潜在信号组织和邻近的肿瘤未完全了解。鉴于肥胖率上升和挑战许多人失去多余的脂肪组织，这是一种有效识别的综合多级方法需要串扰和验证关键分子目标，以制定基于机制的有效策略预防和控制肥胖驱动的CC。我们假设代谢和炎症肥胖引起的扰动通过改变脂肪细胞和结肠之间的信号传导增加了CC风险上皮/肿瘤细胞，并且抑制该串扰会破坏肥胖-CC链接。我们将通过集成：1）独特，前瞻性，多中心流行病学来检验这一假设与肥胖的CC患者的同类群体，从中配对血清，肿瘤和肿瘤脂肪组织样品将用于发现和验证铅靶； 2）瘦的体内互补模型和饮食诱导的肥胖小鼠，以及体外/体内器官模型，其中潜在的靶标肥胖对CC的影响的基础将进行机理测试。这种独特的跨学科方法利用生化，转录组和严格的研究设计中的代谢组学分析，以识别和验证新目标，以破坏脂肪细胞和结肠上皮细胞之间的相互串扰。我们提出了三个协同目标：1a）使用400名CC患者发现并验证脂肪组织-CC连接的基础目标； b）识别和验证脂肪细胞 - 凝结细胞串扰的代谢和转录组特征； 2）表征使用CC的两种严格的小鼠模型，肥胖-CC链路的脂肪细胞 - 固定细胞串扰； 3）到使用肥胖相关的CC进展中候选上皮靶基因的因果作用鼠在体外和体内器官CC模型中。这种范式转移的跨学科合作建立在广泛的初步数据的基础上，并生成通过互补的人类和鼠类研究，最大程度的协同作用，使用相同的最先进跨临床和临床前研究的生物标志物面板和平台。我们预计从这些发现拟议的研究将通过建立因果关系解决与肥胖和CC相关的临床挑战拦截和破坏脂肪细胞上皮细胞串扰的最有希望的目标的链接。