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

改造结肠癌组织以检查肥胖微环境在肿瘤侵袭性中的作用

• 批准号: 10522863
• 负责人: Michael W Greene
• 金额: $ 50.02万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522863
• 关键词: 3-Dimensional; Adipocytes; Adipose tissue; Affect; Beds; Benchmarking; Bioinformatics; Biological Assay; Biomimetics; Cancer Model; Cell Line; Cells; Clinical Data; Clinical Oncology; Colon Adenocarcinoma; Colon Carcinoma; Colorectal Cancer; Complex; Conditioned Culture Media; Consensus; Cues; Disease; Disease Progression; Engineering; Epidemiology; Extracellular Matrix; Gene Expression; Genomics; Growth; Heterogeneity; Human; Implant; In Vitro; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Investigator-Initiated Research; Link; Maintenance; Malignant Neoplasms; Mechanics; Mediating; Metabolic; Metabolic Diseases; Modeling; Morbidity - disease rate; Mus; Obesity; Pathologic; Pathway interactions; Patients; Phenotype; Population; Property; Proteomics; Research; Role; Signal Pathway; Signal Transduction; Stromal Cells; Technology; Testing; The Cancer Genome Atlas; Thinness; Tissue Engineering; Tissues; Transforming Growth Factor beta; Transplantation; Tumor Bank; Validation; anticancer research; base; bioinformatics tool; cancer cell; cancer subtypes; clinical practice; cohort; colon cancer patients; colorectal cancer treatment; flexibility; improved; in vitro Model; in vivo; in vivo Model; model development; molecular subtypes; mortality; patient derived xenograft model; portability; primary outcome; response; skills; systemic inflammatory response; tissue culture; tool; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression; tumor xenograft

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.

摘要 已知调节肿瘤微环境可促进结直肠癌的生长和存活 (CRC)细胞强有力的流行病学证据将某些类型的人类癌症（包括CRC）与肥胖联系起来， 并且肥胖的病理生理状态已经在实验上显示刺激CRC肿瘤生长。然而，在这方面， 涉及的机制还不完全清楚：特别是，肥胖肿瘤微环境对 CRC肿瘤细胞组成、硬度和ECM组成尚不清楚。此外，病理生理学上 用于研究肥胖相关炎症介导的肥胖者变化的相关、患者特定模型， CRC不存在肿瘤微环境。因此，拟议项目的目标是检查调制 肿瘤微环境和肥胖相关的CRC疾病进展使用组织工程患者 通过与患者肿瘤和PDX肿瘤的比较验证了衍生的异种移植（PDX）CRC模型。我们 协作团队将通过利用其独特的跨学科专业知识来实现这一目标 在CRC，组织工程，肥胖和代谢疾病，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，该模型复制了肥胖、胰岛素抵抗/促胰岛素释放的患者中发现的线索。 炎症性肿瘤微环境，以检验肥胖改变肿瘤微环境中基质信号传导的假设。 共有分子亚型4（CMS 4）肿瘤微环境。为了验证我们的假设，我们开发了 一种组织工程化平台，能够长期体外培养患者来源的CRC细胞， 天然肿瘤微环境的重演，特别是基质成分。以下 具体目标：目标1。确定3D体外工程化CMS 4衍生的CRC 组织重现患者和PDX肿瘤;目的2.确定并比较肥胖介导的 CMS 4衍生的3D工程化组织和PDX肿瘤的基质组分和转移特性;以及 目标3.检查来自肥胖CRC患者的3D工程化组织、PDX肿瘤和患者肿瘤， 组织细化和肥胖模型验证。 这一研究工作是为了响应FOA PAR-19-113，癌症组织工程 合作：使仿生组织工程技术用于癌症研究。总的来说，这些努力， 它采用最先进的技术来表征和比较我们的配对模型和人类患者， 以深入和严谨的方式研究肿瘤，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，以便该工具可用于揭示肥胖驱动的CRC亚型特异性机制 肿瘤进展以及影响CRC发病率和死亡率的其他参数。