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

• 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
• 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

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.

总结 肥胖症在全球范围内的流行性上升令人担忧，其中美国的增长率最高。 肥胖是许多癌症类型的主要危险因素，包括结肠癌（CC）。到目前为止，生物 这种关系的潜在机制，特别是失调的脂肪细胞之间的潜在信号传导， 组织和邻近肿瘤，不完全了解。考虑到肥胖率的上升和 许多人失去多余的脂肪组织，一个综合的，多层次的方法，以有效地识别 串扰和验证关键的分子目标，需要开发有效的机制为基础的战略， 预防和控制肥胖驱动的CC。我们假设代谢和炎症 肥胖引起的紊乱通过改变脂肪细胞和结肠之间的信号传导增加CC风险 上皮/肿瘤细胞，抑制这种串扰将破坏肥胖-CC联系。 我们将通过以下整合来检验这一假设：1）一项独特的、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，其中配对的血清、肿瘤和肿瘤旁脂肪 组织样本将用于发现和验证先导靶标;和2）瘦的补充体内模型 和饮食诱导的肥胖小鼠与CC，连同在体外/体内类器官模型，其中潜在的目标 肥胖对CC的潜在影响将被机械地测试。这种独特的跨学科方法 利用创新的临床/流行病学和临床前研究的生物化学，转录组学， 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 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-CC联系的潜在靶标; B）鉴定并 验证脂肪细胞-结肠细胞串扰的代谢和转录组学特征; 2）表征 使用两种严格的CC小鼠模型，研究肥胖-CC联系背后的脂肪细胞-结肠细胞串扰; 3） 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基础上， 通过互补的人类和小鼠研究，使用相同的最先进技术， 跨临床和临床前研究的生物标志物组和平台。我们预计，这些发现 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， 链接的最有前途的目标拦截和破坏脂肪细胞上皮细胞串扰。