Defining the mechanism of inositol 1,4,5-triphosphate receptor-mediated metastatic liver colonization in colorectal cancer

定义肌醇 1,4,5-三磷酸受体介导的结直肠癌转移性肝定植机制

• 批准号: 10283300
• 负责人: Ryan Moy
• 金额: $ 27.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283300
• 关键词: Bioenergetics; Bioinformatics; Biology; Blood Circulation; Calcium; Calcium Signaling; Cancer Etiology; Cancer Model; Cancer Patient; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Cessation of life; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Colorectal Cancer; Cues; Data; Development Plans; Distant; Endoplasmic Reticulum; Environment; Epithelial; Extracellular Matrix; FRAP1 gene; Funding; Generations; Genes; Glucose; Impairment; In Vitro; Injections; Inositol; Laboratories; Link; Liver; Liver parenchyma; Malignant Neoplasms; Mediating; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Metastatic to; Modernization; Molecular; Molecular Biology; NF-kappa B; Neoplasm Metastasis; Nonmetastatic; Nuclear; Oncogenes; Oncology; Organ; Organoids; Outcome; Oxidation-Reduction; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physicians; Physiological; Polyribosomes; Positioning Attribute; Pre-Clinical Model; Primary Neoplasm; Process; Proteins; Proteomics; Research; Role; Sampling; Scientist; Second Messenger Systems; Signal Transduction; Site; Solid; Stress; Systemic Therapy; Testing; Therapeutic; Tissues; Training; Translation Alteration; Translations; United States; Universities; Work; Xenograft procedure; adeno-associated viral vector; base; cancer cell; cancer recurrence; career development; colorectal cancer metastasis; design; experience; experimental study; extracellular; gastrointestinal; genome-wide; improved; improved outcome; in vivo; innovation; insight; member; metabolomics; metastatic colorectal; mortality; mouse model; novel; oncology service; patient derived xenograft model; prevent; promoter; receptor; relB protein; response; ribosome profiling; skills; small hairpin RNA; therapeutic target; therapeutically effective; transcriptome sequencing; tripolyphosphate; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Metastatic progression is the predominant cause of death from solid organ tumors like colorectal cancer but is poorly understood at the molecular level. While modern systemic therapy has incrementally improved outcomes, survival in metastatic colorectal cancer remains dismal, with less than 15 percent of patients alive at five years. Therefore, there is an urgent need to identify and characterize the key genes and pathways that facilitate metastatic colonization. Using a genome-scale in vivo short hairpin RNA (shRNA) screen, the PI and his collaborators have identified several putative metastasis promoters including the type 3 inositol 1,4,5- triphosphate receptor (ITPR3), which mobilizes intracellular calcium from the endoplasmic reticulum. ITPR3 deletion in colorectal cancer cells reduces liver metastatic capacity in vivo, implicating ITPR3 as a key driver of metastasis. Preliminary data suggest that ITPR3 may allow disseminating cancer cells to overcome physiological barriers inherent to the metastatic microenvironment, such as the loss of normal extracellular attachment to the primary epithelial site, potentially through shutting down energetically demanding processes such as protein translation. In addition, ITPR3 may regulate pro-metastatic non-canonical NF-kB signaling and the associated transcription factor RELB, which was also identified as a robust metastasis promoter in the shRNA screen. These studies have led to the hypothesis that ITPR3 is a central coordinator of multiple pathways to support survival during early and late phases of metastatic colonization. Experiments are proposed to (1) define the mechanisms by which ITPR3 regulates translation and cellular metabolism through polysome/ribosome profiling, proteomics and metabolomics, (2) elucidate the mechanism by which ITPR3 controls RELB and non-canonical NF-kB signaling to facilitate metastasis, and (3) determine whether ITPR3 can be therapeutically targeted using novel organoids derived from highly metastatic patient-derived xenografts. Successful completion of the proposed work will improve understanding of the mechanisms underlying metastatic colonization in colorectal cancer and reveal avenues to develop more effective therapeutic strategies to block metastatic progression. The applicant, Dr. Ryan Moy, is a Medical Oncology Fellow and member of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Moy has outlined a 5-year career development plan that expands on his background in molecular biology and clinical training in oncology to acquire vital skills for becoming an independent physician-scientist. He will perform the proposed studies under the mentorship of Dr. Sohail Tavazoie, a physician-scientist and leading expert in metastasis biology with a strong track record of training successful scientists. Dr. Moy will develop new skills in bioinformatics, metabolomics, proteomics and the generation of patient-derived cancer models. In addition to this training plan and strong scientific background, the combined institutional environments of MSKCC and The Rockefeller University ideally position Dr. Moy to successful develop into an independent laboratory-based physician-scientist with R01 funding.

项目摘要/摘要 转移进展是结直肠癌等实体器官肿瘤的主要死亡原因，但 在分子水平上知之甚少。虽然现代系统治疗逐渐改善了结果， 转移性结直肠癌的存活率仍然很低，只有不到15%的患者能活到五年。 因此，迫切需要确定和表征促进 转移性殖民。利用在体基因组规模的短发夹状RNA(ShRNA)筛选，Pi和His 合作者已经确定了几种可能的转移促进剂，包括3型肌醇1，4，5- 三磷酸受体(ITPR3)，它从内质网动员细胞内的钙。ITPR3 结直肠癌细胞中的缺失降低了体内的肝转移能力，暗示ITPR3是 转移。初步数据表明，ITPR3可能允许癌细胞扩散以克服生理性 转移微环境固有的障碍，如失去正常的细胞外附着 初级上皮部位，可能通过关闭蛋白质等耗能高的过程 翻译。此外，ITPR3还可能调节促转移的非典范核因子-kB信号及其相关的 转录因子RELb，在shRNA筛选中也被认为是一个强大的转移启动子。这些 研究表明，ITPR3是支持生存的多条途径的中枢协调者 在转移定植的早期和晚期。建议进行实验以(1)确定机制 ITPR3通过多聚体/核糖体图谱、蛋白质组学等调控翻译和细胞代谢 和代谢组学，(2)阐明了ITPR3控制RELB和非典型性核因子-kB的机制 信号以促进转移，以及(3)确定ITPR3是否可以通过新的 来自高度转移性患者来源的异种移植物的有机类化合物。圆满完成拟议工作 将提高对结直肠癌转移定植机制的理解，并揭示 开发更有效的治疗策略以阻止转移进展的途径。申请者是Dr。 瑞安·莫伊是医学肿瘤学研究员，也是纪念医院胃肠道肿瘤学服务的成员 斯隆凯特琳癌症中心(MSKCC)。莫伊博士概述了一项为期5年的职业发展计划，该计划将扩大 关于他在分子生物学和肿瘤学临床培训方面的背景，以获得成为一名 独立的医生兼科学家。他将在索海尔博士的指导下进行拟议的研究 Tavazoie是一位内科科学家和转移生物学方面的领先专家，有良好的培训记录 成功的科学家。莫伊博士将在生物信息学、代谢组学、蛋白质组学和 生成患者来源的癌症模型。除了这个培训计划和强大的科学背景， MSKCC和洛克菲勒大学的联合机构环境使莫伊博士能够 成功发展成为一家独立的以实验室为基础的内科科学家，拥有R01资金。