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

摘要 肥胖症在全球范围内的普遍上升令人担忧，其中最高的增幅发生在美国。 肥胖是许多癌症类型的主要风险因素，包括结肠癌(CC)。到目前为止，生物界 这种关系的潜在机制，特别是调节失调的脂肪之间的潜在信号 组织和邻近肿瘤，是不完全了解的。鉴于肥胖率的上升和面临的挑战 对于许多人来说，要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 需要串扰和验证关键分子目标来开发有效的基于机制的策略 预防和控制肥胖驱动的CC。我们假设新陈代谢和炎症 肥胖引起的扰动通过改变脂肪细胞和结肠之间的信号来增加CC风险 上皮细胞/肿瘤细胞，抑制这种串扰将扰乱肥胖与CC的联系。 我们将通过以下整合来检验这一假设：1)独特的、前瞻性的、多中心的流行病学 体重正常的肥胖CC患者的队列，从他们那里配对血清、肿瘤和肿瘤邻近脂肪 组织样本将被用来发现和验证铅靶标；以及2)补充体内瘦肉模型 和饮食诱导的肥胖小鼠的CC，以及在体外/体内的有机模型中潜在的靶点 肥胖对CC的潜在影响将从机械上进行测试。这种独特的跨学科方法 利用创新的临床/流行病学和临床前生化、转录本和 严格研究设计中的代谢组学分析，以确定和验证扰乱 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：1) 使用400名CC患者，发现和验证脂肪组织-CC链接的潜在靶点；b)识别和 验证脂肪细胞-结肠细胞串扰的代谢和转录特征；2)表征 肥胖-CC联系的脂肪细胞-结肠细胞串扰，使用两种严格的CC小鼠模型；3) 确定候选上皮靶基因在肥胖相关CC进展中的因果作用 小鼠体外和体内有机类CC模型的建立。 这种改变范式的跨学科协作建立在广泛的初步数据基础上，并生成 通过互补的人类和小鼠研究，使用相同的最先进技术，最大限度地发挥协同作用 跨越临床和临床前研究的生物标记物面板和平台。我们期待从这些发现中 拟议的研究将通过确定原因，解决与肥胖和CC相关的临床挑战 最有希望拦截和破坏脂肪细胞-上皮细胞串扰的目标的链接。

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.