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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要转移进展是结直肠癌等实体器官肿瘤死亡的主要原因，但在分子水平上了解甚少。虽然现代全身治疗已逐渐改善结果，转移性结直肠癌的生存率仍然很低，只有不到 15% 的患者五年后仍能存活。因此，迫切需要识别和表征促进这一过程的关键基因和途径。转移定植。使用基因组规模的体内短发夹 RNA (shRNA) 筛选，PI 和他的团队合作者已经确定了几种假定的转移促进剂，包括 3 型肌醇 1,4,5- 三磷酸受体（ITPR3），从内质网动员细胞内钙。 ITPR3 结直肠癌细胞中的缺失降低了体内肝转移能力，这表明 ITPR3 是肝脏转移能力的关键驱动因素。转移。初步数据表明，ITPR3 可能使传播的癌细胞克服生理学障碍。转移微环境固有的障碍，例如正常细胞外附着的丧失主要上皮位点，可能通过关闭蛋白质等能量要求较高的过程翻译。此外，ITPR3 可能调节促转移的非经典 NF-kB 信号传导和相关的转录因子 RELB，在 shRNA 筛选中也被鉴定为强大的转移启动子。这些研究得出这样的假设：ITPR3 是支持生存的多种途径的中央协调者在转移定植的早期和晚期阶段。建议进行实验（1）定义机制 ITPR3 通过多核糖体/核糖体分析、蛋白质组学调节翻译和细胞代谢和代谢组学，（2）阐明ITPR3控制RELB和非经典NF-kB的机制信号传导以促进转移，以及（3）确定 ITPR3 是否可以使用新型药物进行治疗靶向源自高度转移的患者异种移植物的类器官。成功完成拟议工作将增进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来阻止转移进展的途径。申请人，博士。 Ryan Moy，是纪念医院肿瘤内科研究员和胃肠肿瘤服务成员斯隆凯特琳癌症中心 (MSKCC)。莫伊博士概述了一个 5 年职业发展计划，该计划扩展了凭借他在分子生物学和肿瘤学临床培训方面的背景，获得成为一名独立医师科学家。他将在 Sohail 博士的指导下进行拟议的研究 Tavazoie，一位医师科学家和转移生物学领域的领先专家，拥有丰富的培训记录成功的科学家。莫伊博士将开发生物信息学、代谢组学、蛋白质组学和产生源自患者的癌症模型。除了这个培训计划和强大的科学背景之外， MSKCC 和洛克菲勒大学的综合机构环境使莫伊博士能够理想地在 R01 资助下成功发展成为以独立实验室为基础的医师科学家。