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: 10696161
• 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/10696161
• 关键词: Bioenergetics; Bioinformatics; Biology; Calcium; Calcium Signaling; Cancer Etiology; Cancer Model; Cancer Patient; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Cessation of life; Circulation; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Colorectal Cancer; Cues; DCC gene; Data; Development Plans; Distant; Endoplasmic Reticulum; Environment; Epithelium; Extracellular Matrix; FRAP1 gene; Funding; Generations; Genes; Glucose; Impairment; In Vitro; Injections; Inositol; Institution; Laboratories; Link; Liver; Liver parenchyma; Malignant Neoplasms; Mediating; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Modernization; Molecular; Molecular Biology; NF-kappa B; Neoplasm Metastasis; Nuclear; 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; Recurrent Malignant Neoplasm; Research; Role; Sampling; Scientist; Second Messenger Systems; Signal Transduction; Site; Solid; Stress; Systemic Therapy; Testing; Therapeutic; Tissues; Training; Translations; United States; Universities; Work; Xenograft procedure; adeno-associated viral vector; cancer cell; cancer recurrence; career development; clinical training; colorectal cancer metastasis; delivery vehicle; 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 转移性进展是固体器官肿瘤（如结直肠癌）的主要死亡原因，但 在分子水平上了解不足。虽然现代的全身疗法逐渐改善了预后，但 转移性结直肠癌的生存仍然令人沮丧，五年来还不到15％的患者。 因此，迫切需要识别和表征促进的关键基因和途径 转移性定殖。使用基因组规模在体内短发夹RNA（shRNA）屏幕，PI和他的 合作者已经确定了几个推定的转移启动子，包括3型肌醇1,4,5-- 三磷酸受体（ITPR3），该受体动员内质网的细胞内钙。 ITPR3 结直肠癌细胞的删除可降低体内肝转移能力，这意味着ITPR3是 转移。初步数据表明ITPR3可能允许传播癌细胞克服生理 转移性微环境固有的障碍，例如失去正常的细胞外附着 原发性上皮部位，有可能通过关闭能量要求的过程，例如蛋白质 翻译。此外，ITPR3可能调节促旋转非循环NF-KB信号和相关的 转录因子RELB，在shRNA筛选中也被鉴定为可靠的转移启动子。这些 研究导致了以下假设：ITPR3是支持生存的多种途径的中心协调员 在转移性定殖的早期和晚期。提出实验以（1）定义机制 ITPR3通过多元素/核糖体分析，蛋白质组学调节翻译和细胞代谢 （2）阐明ITPR3控制RELB和非典型NF-KB的机制 信号传导以促进转移，（3）确定是否可以使用新颖的ITPR3进行治疗 源自高度转移性患者衍生异种移植物的器官。成功完成拟议的工作 将提高对结直肠癌转移性定植机制的理解，并揭示 制定更有效的治疗策略以阻止转移性进展的途径。申请人，博士 瑞安·莫伊（Ryan Moy）是一名医学肿瘤学研究员，也是纪念馆胃肠道肿瘤学服务的成员 斯隆开氏癌中心（MSKCC）。 Moy博士概述了一项为期5年的职业发展计划，该计划扩大了 在他在分子生物学和肿瘤学临床培训方面的背景下，获得了重要的技能 独立的医师科学家。他将在Sohail博士的指导下进行拟议的研究 塔瓦佐（Tavazoie），医师科学家，转移生物学领域的领先专家，培训的记录很强 成功的科学家。 Moy博士将发展生物信息学，代谢组学，蛋白质组学和The的新技能 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外， MSKCC和洛克菲勒大学的合并机构环境理想地将Moy博士定位为 成功发展为具有R01资金的独立基于实验室的医师科学家。

项目成果

A nutritional management algorithm in older patients with locally advanced esophageal cancer.

• DOI: 10.1016/j.jgo.2021.06.012
• 发表时间: 2022-01
• 期刊: JOURNAL OF GERIATRIC ONCOLOGY
• 影响因子: 3
• 作者: Moy, Ryan H.;Sabwa, Shalom;Maron, Steven B.;Shcherba, Marina;Apollo, Arlyn;Janjigian, Yelena Y.;Ku, Geoffrey Y.;Tew, William P.;Wu, Abraham J.;Jones, David R.;Molena, Daniela;Ilson, David H.;Won, Elizabeth
• 通讯作者: Won, Elizabeth