Engineered Colon Cancer Tissue to Examine the Role of the Obese Microenvironment in Tumor Aggressiveness

摘要 已知肿瘤微环境的调节可促进结直肠癌的生长和生存 (CRC)信元。强有力的流行病学证据表明，包括CRC在内的某些类型的人类癌症与肥胖有关， 实验表明，肥胖的病理生理状态可以刺激结直肠癌的生长。然而， 其中涉及的机制尚不完全清楚：尤其是肥胖的肿瘤微环境对 结直肠癌的细胞成分、硬度和细胞外基质成分尚不清楚。此外，在病理生理学上 相关的，特定于患者的模型，用于研究肥胖相关的炎症介导的肥胖者的变化， 结直肠癌不存在肿瘤微环境。因此，拟议项目的目标是检查调制 利用组织工程患者研究肿瘤微环境与肥胖相关的结直肠癌疾病进展 衍生异种移植(PDX)结直肠癌模型通过与患者肿瘤和PDX肿瘤的比较而得到验证。我们的 协作团队将通过利用他们独特的跨学科专业知识来实现这一目标 结直肠癌、组织工程、肥胖和代谢性疾病、转录组学、蛋白质组学和生物信息学。 我们将使用我们改进的CRC模型，复制在肥胖、胰岛素抵抗/亲合者中发现的线索。 炎性肿瘤微环境测试肥胖改变肿瘤间质信号的假说 共识分子亚型4(CMS4)肿瘤微环境。为了检验我们的假设，我们开发了 一种组织工程平台，能够长期体外培养患者来源的CRC细胞和 自然肿瘤微环境，特别是间质成分的概述。以下是 将追求特定的目标：目标1.确定3D体外工程CMS4来源的CRC的程度 组织总结患者和PDX肿瘤；目的2：确定和比较肥胖在 CMS4来源的3D工程组织和PDX肿瘤的间质成分和转移特性；以及 目的3.检查3D工程组织、PDX肿瘤和肥胖结直肠癌患者的肿瘤 组织精细化和肥胖模型验证。 这项由研究人员发起的研究工作是对FOA PAR-19-113，癌症组织工程的回应 合作：为癌症研究启用仿生组织工程技术。总的来说，这些努力， 它使用最先进的技术来描述和比较我们的配对模型和人类患者 在肿瘤的深入和严谨的方式下，将开发一个具有强大功能的便携式组织工程平台 交叉验证使该工具可以用来揭示CRC亚型特定的肥胖驱动机制 肿瘤进展以及影响结直肠癌发病率和死亡率的其他参数。

Abstract Modulation of the tumor microenvironment is known to promote the growth and survival of colorectal cancer (CRC) cells. Strong epidemiological evidence links certain types of human cancer, including CRC, with obesity, and the obese pathophysiological state has been shown experimentally to stimulate CRC tumor growth. However, the mechanisms involved are not fully known: in particular, the impact of the obese tumor microenvironment on CRC tumor cellular composition, stiffness, and ECM composition is not known. Further, pathophysiologically relevant, patient-specific models for investigating obesity-linked inflammation mediated changes in the obese, tumor microenvironment do not exist for CRC. Thus, the objective of the proposed project is to examine modulation of the tumor microenvironment and obesity-related CRC disease progression using tissue-engineered patient derived xenograft (PDX) CRC models validated through comparison to patient tumors and PDX tumors. Our collaborative team will achieve this objective by leveraging their unique combined interdisciplinary expertise in CRC, tissue engineering, obesity and metabolic disease, transcriptomics, proteomics, and bioinformatics. We will use our improved models of CRC that replicate the cues found in the obese, insulin resistant/pro- inflammatory tumor microenvironment to test the hypothesis that obesity alters stromal signaling in the consensus molecular subtype 4 (CMS4) tumor microenvironment. To test our hypothesis, we have developed a tissue-engineered platform that enables long-term in vitro culture of the patient-derived CRC cells and recapitulation of the native tumor microenvironment, particularly the stromal component. The following Specific Aims will be pursued: Aim 1. Determine the extent to which 3D in vitro engineered CMS4-derived CRC tissues recapitulate patient and PDX tumors; Aim 2. Determine and compare the obesity mediated changes in the stromal component and metastatic properties of CMS4-derived 3D engineered tissues and PDX tumors; and Aim 3. Examine 3D engineered tissues, PDX tumors, and patient tumors from obese CRC patients for engineered tissue refinement and obesity model validation. This investigator-initiated research effort is in response to FOA PAR-19-113, Cancer Tissue Engineering Collaborative: Enabling Biomimetic Tissue-Engineered Technologies for Cancer Research. Overall, these efforts, which employ state-of-the-art technologies to characterize and compare our paired models and human patient tumors in an in-depth and rigorous manner, will develop a portable tissue-engineering platform with robust cross-validation so that this tool can be used to uncover CRC subtype specific mechanisms of obesity-driven tumor progression, as well as other parameters affecting CRC morbidity and mortality.