The Role of Long Non-coding RNAs in EMT and Cancer Stem Cells

长非编码 RNA 在 EMT 和癌症干细胞中的作用

• 批准号: 8891190
• 负责人: Jason I Herschkowitz
• 金额: $ 24.15万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891190
• 关键词: Adherens Junction; Architecture; Area; Biological; Biological Models; Biological Process; Breast; Breast Cancer Model; Breast Epithelial Cells; Cancer Center; Cell model; Cells; Chromatin; Clinic; Clinical; Code; Collaborations; Colon Carcinoma; Complex; Core Facility; Development; Doctor of Medicine; E-Cadherin; ERBB2 gene; Environment; Epigenetic Process; Epithelial Cells; Faculty; Fellowship; Gene Expression; Gene Expression Profiling; Genes; Genetically Engineered Mouse; Genome; Genomics; Goals; Heart; Hospitals; Human; Human Characteristics; Institution; Knowledge; Laboratories; Learning; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Mediating; Medical center; Medicine; Mentors; Mentorship; Mesenchymal; Methodist Church; MicroRNAs; Modeling; Modification; Molecular; Molecular and Cellular Biology; Multiprotein Complexes; Mus; Neoadjuvant Therapy; Pathway interactions; Phenotype; Play; Postdoctoral Fellow; Process; Property; Proteins; RNA; Regulation; Research; Research Institute; Research Personnel; Research Training; Resistance; Resources; Rice; Role; Solid; Source; Stem Cell Research; Stem cells; Stimulus; Subgroup; Testing; Texas; Tight Junctions; Training; Transcript; Transcriptional Regulation; Translating; Universities; Untranslated RNA; Walking; Work; aggressive therapy; calin; cancer cell; cancer genomics; cancer stem cell; career; chemotherapy; claudin 3; clinically relevant; college; combat; conventional therapy; differential expression; epigenetic regulation; epithelial to mesenchymal transition; graduate student; improved; insight; malignant breast neoplasm; mammalian genome; mammary gland development; medical schools; mouse model; neoplastic cell; pre-clinical; programs; radioresistant; screening; skills; stem cell population; targeted treatment; therapy resistant; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT Candidate Dr. Jason Herschkowitz began his research career as a graduate student in the laboratory of Dr. Charles Perou at UNC Chapel Hill. His research focus was on a large-scale genomic comparison of human breast cancer subtypes and genetically engineered mouse mammary tumor models. This study showed that although no single mouse model recapitulated all the expression features of a given human subtype, many of the defining characteristics of the human subtypes were conserved among the mouse models providing insight for their preclinical applications. Jason then moved to the Baylor College of Medicine (BCM) as a postdoctoral fellowship in Dr. Jeffrey Rosen's laboratory. There he has concentrated on studying the claudin-low subtype of breast cancer initially identified in his graduate work. Using a unique mouse model, he has determined that claudin-low tumors are enriched for functional cancer stem cells (CSCs) compared to tumors of other subtypes arising in this model. Jason's graduate training has provided him with an expertise in cancer genomics and mouse models. His postdoctoral work has given him the knowledge and skills involved in stem cell research, mammary gland development, and tumorigenesis. Jason's short-term career goals are to now take what he has learned and apply it to the field of long non-coding RNAs (lncRNAs). In order to receive training in this new area, Jason has identified two additional outstanding co-mentors in Dr. Howard Chang and Dr. George Calin. The goal of the next two years is for Jason to receive the additional research training necessary to tackle this new research area as well as valuable career mentorship to prepare him for a successful career as an independent investigator at a highly ranked academic institution. Environment Jason is a postdoctoral fellow in the laboratory of Dr. Jeffrey Rosen in the department of Molecular and Cellular Biology, part of the Dan L. Duncan Cancer Center and the Breast Research Program of the Lester and Sue Smith Breast Center. BCM is an outstanding environment for trainees to develop the necessary skills to become successful independent researchers. The college has exceptional faculty, centers, and state of the art core facilities. BCM is located in the heart of the Texas Medical Center and is walking distance to several outstanding research and clinical institutions including M.D. Anderson Cancer Center, UT Houston Medical School, Rice University, and the Methodist Hospital Research Institute. These institutions serve as additional scientific resources, sources of collaboration, and seminars. Research Gene expression profiling has been used to classify human breast tumors into distinct, clinically- relevant subgroups, including a rare molecular subtype referred to as claudin-low. Compared to tumors of other subtypes, claudin-low tumors have lower expression of tight and adherens junction genes, including claudin 3 and E-cadherin, and higher expression of epithelial to mesenchymal transition (EMT) associated genes. We recently found that claudin-low tumors are enriched for functional CSCs. It has been determined that inducing EMT in human mammary epithelial cells endows them with stem cell-like properties. Together these lines of evidence suggest important molecular and biological links between EMT and the CSC-enriched claudin-low tumors. Recent studies suggest that the majority of the genome is transcribed even though less than 2% of the mammalian genome is occupied by coding regions. These transcripts are called non-coding RNAs (ncRNAs) because they have no protein coding capacity. There has been a great deal of focus on the role of a class of small ncRNAs, called miRNAs, in development and cancer. In contrast, much less is known about the vast majority of transcripts represented by lncRNAs. One recent theme is that many lncRNAs function through interactions with chromatin modifying complexes and control chromatin architecture. While a variety of functional roles for lncRNAs have been implicated in many biological processes, only in relatively few cases have these been well defined. The precise mechanistic details of lncRNA function remain a mystery that needs exploration. As might be expected from the roles of lncRNAs in transcriptional regulation, epigenetic modifications, and development, there is increasing evidence of the misregulation of lncRNAs in cancer. Several groups, including ours, have shown that breast CSCs are more resistant to radiation and chemotherapy compared to non-CSCs. We hypothesize lncRNAs play a critical role in an EMT gene expression program governed in part by RNA-mediated epigenetic regulation leading to resistance to conventional therapies in breast cancer. An improved understanding of the molecular networks responsible for the EMT/CSC phenotype is critical for defining targets for combating the therapeutic resistance of CSCs, which may be especially pertinent to claudin-low tumors. The goal of this project, using several model systems and a strategy for large-scale functional screening, is to first identify and then investigate the mechanisms of action of lncRNAs that regulate the EMT/CSC phenotype of claudin-low breast tumors.

项目概要/摘要 候选人 Jason Herschkowitz 博士作为研究生在 Dr. Jason Herschkowitz 实验室开始了他的研究生涯。 查尔斯·佩鲁 (Charles Perou) 在北卡罗来纳大学教堂山分校。他的研究重点是人类基因组的大规模比较 乳腺癌亚型和基因工程小鼠乳腺肿瘤模型。这项研究表明 尽管没有一个小鼠模型能够概括特定人类亚型的所有表达特征，但许多 人类亚型的定义特征在小鼠模型中得到保留，提供了洞察力 用于其临床前应用。随后 Jason 前往贝勒医学院 (BCM) 担任博士后 Jeffrey Rosen 博士实验室的研究员。在那里，他专注于研究claudin-low亚型 乳腺癌最初是在他的研究生工作中发现的。使用独特的小鼠模型，他确定 与其他亚型的肿瘤相比，紧密连接蛋白低的肿瘤富含功能性癌症干细胞 (CSC) 出现在这个模型中。 Jason 的研究生培训为他提供了癌症基因组学和 鼠标模型。他的博士后工作使他获得了干细胞研究方面的知识和技能， 乳腺发育和肿瘤发生。杰森的短期职业目标是现在采取他的 已经学习并将其应用到长非编码RNA（lncRNA）领域。为了接受这方面的培训 在新领域，Jason 又确定了两位杰出的共同导师：Howard Chang 博士和 George 博士 卡林.未来两年的目标是杰森接受必要的额外研究培训 解决这个新的研究领域以及宝贵的职业指导，帮助他为成功的职业生涯做好准备 排名靠前的学术机构的独立调查员。 环境 Jason 是 Jeffrey Rosen 博士实验室的分子与生物学系的博士后研究员。 细胞生物学，丹·L·邓肯癌症中心和莱斯特和乳腺研究计划的一部分 苏·史密斯乳腺中心。 BCM 为学员提供了一个培养必要技能的绝佳环境 成为成功的独立研究人员。学院拥有卓越的师资、中心和最先进的设施 核心设施。 BCM 位于德克萨斯医疗中心的中心地带，步行即可到达几个 杰出的研究和临床机构，包括 M.D. Anderson 癌症中心、UT Houston Medical 学院、莱斯大学和卫理公会医院研究所。这些机构作为额外的 科学资源、合作来源和研讨会。 研究 基因表达谱已用于将人类乳腺肿瘤分类为不同的、临床上的肿瘤类型。 相关亚组，包括一种罕见的分子亚型，称为claudin-low。与肿瘤相比 其他亚型，claudin-low 肿瘤的紧密连接和粘附连接基因表达较低，包括 密蛋白 3 和 E-钙粘蛋白，以及上皮间质转化 (EMT) 相关的较高表达 基因。我们最近发现，claudin 低的肿瘤富含功能性 CSC。已经确定了 在人类乳腺上皮细胞中诱导 EMT 赋予它们类似干细胞的特性。一起 这些证据表明 EMT 和富含 CSC 之间存在重要的分子和生物学联系 密蛋白低肿瘤。 最近的研究表明，尽管只有不到 2%，但大部分基因组都被转录了。 哺乳动物基因组被编码区占据。这些转录本称为非编码 RNA (ncRNA) 因为它们没有蛋白质编码能力。人们非常关注一类人的作用 小 ncRNA（称为 miRNA）在发育和癌症中的作用。相比之下，人们对这片广阔的土地知之甚少。 大多数转录本由lncRNA 代表。最近的一个主题是许多 lncRNA 通过 与染色质修饰复合物相互作用并控制染色质结构。虽然各种 lncRNA 的功能作用与许多生物过程有关，但仅在相对少数的情况下 这些是否已得到明确定义？ lncRNA功能的精确机制细节仍然是一个谜 需要探索。正如从 lncRNA 在转录调控中的作用所预期的那样，表观遗传 随着修饰和发展，越来越多的证据表明癌症中 lncRNA 的失调。 包括我们在内的几个研究小组已经表明，乳腺 CSC 具有更强的抗辐射能力，并且 与非 CSC 相比，化疗。我们假设 lncRNA 在 EMT 基因中发挥关键作用 表达程序部分受RNA介导的表观遗传调控，导致抗性 乳腺癌的常规疗法。更好地了解负责的分子网络 EMT/CSC 表型对于确定对抗 CSC 治疗耐药的靶点至关重要， 可能与密蛋白低的肿瘤特别相关。该项目的目标是使用多个模型系统和 大规模功能筛选的策略是首先识别然后研究其作用机制 调节claudin-low乳腺肿瘤EMT/CSC表型的lncRNA。