Dietary Regulation of Colon Cancer Metastasis

结肠癌转移的饮食调节

• 批准号: 10366095
• 负责人: Swagata Goswami
• 金额: $ 9.38万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366095
• 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 process; Cell Fate Control; Cell Line; Cell Survival; Cells; Cellular biology; Cessation of life; Colonoscopy; Colorectal Cancer; Cytometry; DNA Damage; DNA Repair; Data; Diet; Differentiation and Growth; Disease; Disease Progression; Disseminated Malignant Neoplasm; Epithelial; Flow Cytometry; GADD45 protein; Genetic; Genetic Engineering; Goals; Growth; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; High Fat Diet; Homeostasis; Human Characteristics; Human Engineering; In Vitro; Incidence; Intestines; Knowledge; Lead; Leukemic Cell; Link; Liver; Malignant Neoplasms; Mediating; Mesenchymal; Metabolic; Metastatic Neoplasm to the Liver; Metastatic to; Mind; 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; Process; Prognosis; Protein phosphatase; RNA Interference; RUNX3 gene; Regulation; Research; Research Project Grants; Research Proposals; Resistance; Retinoblastoma; Role; Safety; Shapes; Signal Transduction; Small Interfering RNA; System; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transplantation; Tretinoin; Tumor Suppressor Proteins; Work; acute myeloid leukemia cell; base; 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; 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; therapeutic target; 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.

项目总结/文摘