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.

概括全球范围内肥胖率的普遍上升令人震惊，其中美国的增幅最高。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，生物这种关系背后的机制，特别是失调的脂肪之间的潜在信号传导组织和邻近肿瘤的情况尚不完全清楚。鉴于肥胖率上升和挑战对于许多人来说，失去多余的脂肪组织，一种综合的、多层次的方法可以有效地识别需要串扰并验证关键分子靶标，以制定有效的基于机制的策略预防和控制肥胖引起的 CC。我们假设代谢和炎症肥胖引起的干扰通过改变脂肪细胞和结肠之间的信号传导而增加 CC 风险上皮细胞/肿瘤细胞，抑制这种串扰将破坏肥胖与 CC 的联系。我们将通过整合以下内容来检验这一假设：1）独特的、前瞻性的、多中心的流行病学研究正常体重至肥胖 CC 患者队列，将血清、肿瘤和肿瘤邻近脂肪配对组织样本将用于发现和验证先导目标； 2）补充精益体内模型和饮食诱导的患有 CC 的肥胖小鼠，以及潜在目标的体外/体内类器官模型肥胖对 CC 的潜在影响将得到机械测试。这种独特的跨学科方法利用生物化学、转录组学和生物化学的创新临床/流行病学和临床前研究在严格的研究设计中进行代谢组学分析，以确定和验证破坏代谢的新目标脂肪细胞和结肠上皮细胞之间的相互串扰。我们提出三个协同目标：1a) 使用 400 名 CC 患者发现并验证脂肪组织与 CC 联系的潜在目标； b) 识别和验证脂肪细胞-结肠细胞串扰的代谢和转录组特征； 2）表征使用两种严格的 CC 小鼠模型，了解肥胖与 CC 关联背后的脂肪细胞-结肠细胞串扰； 3）到使用以下方法确定候选上皮靶基因在肥胖相关 CC 进展中的因果作用小鼠体外和体内类器官 CC 模型。这种范式转变的跨学科合作建立在广泛的初步数据的基础上，并产生通过互补的人类和小鼠研究，使用相同的最先进技术，实现最大程度的协同作用跨临床和临床前研究的生物标志物组合和平台。我们预计这些研究结果拟议的研究将通过建立因果关系来解决与肥胖和 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联系。