Dietary Regulation of Colon Cancer Metastasis

结肠癌转移的饮食调节

• 批准号: 10621185
• 负责人: Swagata Goswami
• 金额: $ 9.85万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-01-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621185
• 关键词: Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Apoptosis; Automobile Driving; CD34 gene; Cancer Etiology; Cancer Model; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Differentiation Induction; Cell Differentiation process; Cell Fate Control; Cell Line; Cell Survival; Cells; Cellular biology; Cessation of life; Colonoscopy; Colorectal Cancer; Cytometry; DNA Damage; DNA Repair; DNA Repair Inhibition; Data; Diet; Differentiation Therapy; Differentiation and Growth; Disease; Disease Progression; Disseminated Malignant Neoplasm; Epithelium; Flow Cytometry; GADD45 protein; Genetic; Genetic Engineering; Goals; Growth; Health; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; High Fat Diet; Homeostasis; Human Characteristics; Human Engineering; In Vitro; Incidence; Intestines; Knowledge; Leukemic Cell; Link; Liver; Malignant Neoplasms; Mediating; Mesenchymal; Metabolic; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Abnormality; Mus; Mutation; Myelogenous; Neoplasm Metastasis; Nonmetastatic; Obesity; Oncogenes; Oncogenic; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Postdoctoral Fellow; Process; Prognosis; Proliferating; Protein phosphatase; RNA Interference; RUNX3 gene; Regulation; Repression; Research; Research Project Grants; Research Proposals; Resistance; Retinoblastoma; Role; Safety; Shapes; Signal Transduction; Small Interfering RNA; System; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutically Targetable; Transplantation; Tretinoin; Tumor Suppressor Proteins; Work; acute myeloid leukemia cell; base editing; c-myc Genes; cancer cell; cell behavior; clinically relevant; colon cancer metastasis; colon cancer patients; colorectal cancer metastasis; design; diet-induced obesity; dietary; effective therapy; genetic manipulation; genome-wide; in vivo; in vivo Model; inhibitor; inhibitor therapy; insight; interest; kinase inhibitor; leukemia; leukemia treatment; leukemic stem cell; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; oncoprotein p21; organoid transplantation; overexpression; pre-clinical; public health relevance; repaired; research clinical testing; response; skills; stem cell population; stem cells; tool; transcription factor; transcriptome sequencing; transcriptomics; tumor; tumor microenvironment; tumorigenesis; validation studies

Project Summary/Abstract Colorectal cancer (CRC) is the third most frequent cancer worldwide with increasing incidences every year. It is the leading cause of cancer related mortality, predominantly due to metastatic disease. CRC majorly metastasizes to the liver, and almost 30% of CRC patients develop hepatic metastasis resulting in severely poor outcomes and limited treatment options outside of surgery. Our overarching objective is to examine how CRC cells metastasize and adapt to the liver microenvironment in physiologically relevant, organoid transplantation based CRC models that harbor genetic abnormalities commonly found in CRC patients. Our understanding of how the liver microenvironment shapes the responses of the tumor cells is significantly impeded by a lack of in-vivo CRC models that recapitulate metastatic disease. To overcome the limitations of the current CRC models, we propose the use of a murine model utilizing colonoscopy guided orthotopic transplantation of genetically engineered organoids. We have identified that these models faithfully reproduce the characteristics of human CRC, including liver metastasis commonly observed in patients. Using CRISPER/Cas9 based editing, we will genetically engineer human and murine CRC organoids bearing mutations associated with poor prognosis in patients. We will use our in-vivo model to generate pro and non-metastatic lines from these organoids, followed by characterization of the differential molecular changes in the tumor cells and microenvironment that influence disease progression. Our preliminary data shows the differential regulation of epithelial to mesenchymal (EMT) transcription factors such as Twist1 in pro-metastatic organoids as compared to non-metastatic organoids. We will characterize the role of these candidate EMT transcription factors in CRC liver metastasis (Aim 1), and identify molecular mechanisms that differentiate metastatic from non-metastatic tumor cells. Aim 2 of our proposal will study the effect of high fat diet (HFD)-mediated obesity on liver metastasis in CRC. HFD and obesity have been increasingly shown to influence intestinal stem cell behavior and tumorigenesis, however, its influence on disease progression and metastasis remains unknown. Using our CRC in-vivo models, transcriptomic sequencing and functional validation studies, we will dissect the molecular effects of a high fat diet on tumor and liver microenvironment, liver metastasis and overall outcome. Public/Health/Relevance: Successful completion of this study will identify mechanisms integral to initiate and maintain metastasis as well as the role of HFD-induced obesity in this process, revealing therapeutically targetable vulnerabilities in physiologically relevant models of CRC.

项目概要/摘要 结直肠癌（CRC）是全球第三大常见癌症，发病率逐年增加。它是癌症相关死亡的主要原因，主要是由于转移性疾病。结直肠癌主要转移至肝脏，近 30% 的结直肠癌患者会发生肝转移，导致预后严重不佳，手术以外的治疗选择也有限。我们的首要目标是研究 CRC 细胞如何在生理相关的、基于类器官移植的 CRC 模型中转移和适应肝脏微环境，这些模型包含 CRC 患者中常见的遗传异常。 由于缺乏概括转移性疾病的体内结直肠癌模型，我们对肝脏微环境如何影响肿瘤细胞反应的理解受到严重阻碍。为了克服当前结直肠癌模型的局限性，我们建议使用小鼠模型，利用结肠镜检查引导基因工程类器官的原位移植。我们发现这些模型忠实地再现了人类结直肠癌的特征，包括患者中常见的肝转移。使用基于 CRISPER/Cas9 的编辑，我们将对人类和小鼠 CRC 类器官进行基因工程改造，这些类器官带有与患者不良预后相关的突变。我们将使用我们的体内模型从这些类器官中生成促转移细胞系和非转移细胞系，然后表征肿瘤细胞和影响疾病进展的微环境中的差异分子变化。我们的初步数据显示，与非转移性类器官相比，促转移性类器官中上皮间质 (EMT) 转录因子（例如 Twist1）的差异调节。我们将描述这些候选 EMT 转录因子在 CRC 肝转移中的作用（目标 1），并确定区分转移性肿瘤细胞和非转移性肿瘤细胞的分子机制。我们提案的目标 2 将研究高脂饮食 (HFD) 介导的肥胖对结直肠癌肝转移的影响。越来越多的研究表明，高脂肪饮食和肥胖会影响肠道干细胞行为和肿瘤发生，但其对疾病进展和转移的影响仍不清楚。利用我们的 CRC 体内模型、转录组测序和功能验证研究，我们将剖析高脂肪饮食对肿瘤和肝脏微环境、肝转移和总体结果的分子影响。公共/健康/相关性：这项研究的成功完成将确定启动和维持转移的必要机制以及 HFD 诱导的肥胖在此过程中的作用，揭示 CRC 生理相关模型中治疗目标的脆弱性。

项目成果

ROR1 targeted immunoliposomal delivery of OSU-2S shows selective cytotoxicity in t(1;19)(q23;p13) translocated B-cell acute lymphoblastic leukemia.

OSU-2S 的 ROR1 靶向免疫脂质体递送在 t(1;19)(q23;p13) 易位 B 细胞急性淋巴细胞白血病中显示出选择性细胞毒性。

• 发表时间: 2022-07
• 影响因子: 2.7
• 作者: Goswami, Swagata;Chiang, Chi;Zapolnik, Kevan;Nunes, Jessica;Ventura, Ann;Mo, Xiaokui;Xie, Zhiliang;Lee, L James;Baskar, Sivasubramanian;Rader, Christoph;Byrd, John C;Phelps, Mitch;Bhatnagar, Bhavana;Muthusamy, Natarajan
• 通讯作者: Muthusamy, Natarajan