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: 8384595
• 负责人: Jason I Herschkowitz
• 金额: $ 16.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384595
• 关键词: Adherens Junction; Architecture; Area; Biological; Biological Models; Biological Process; Breast; Breast Cancer Model; 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; Functional RNA; 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; Mammary gland; Mediating; Medical center; Medicine; Mentors; Mentorship; Mesenchymal; Methodist Church; Modeling; Modification; Molecular; Molecular and Cellular Biology; Multiprotein Complexes; Mus; Neoadjuvant Therapy; Pathway interactions; Phenotype; Play; Postdoctoral Fellow; Process; Property; Proteins; RNA; Radiation; Regulation; Research; Research Institute; Research Personnel; Research Training; Resistance; Resources; Rice; Role; Screening procedure; Solid; Source; Stem Cell Research; Stem cells; Stimulus; Subgroup; Testing; Texas; Therapeutic; Tight Junctions; Training; Transcript; Transcriptional Regulation; Translating; Universities; Walking; Work; aggressive therapy; calin; cancer cell; cancer genomics; cancer stem cell; career; chemotherapy; claudin 3; clinically relevant; college; combat; conventional therapy; 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; skills; stem cell population; therapy resistant; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Completing the goals of this proposal will enhance our understanding of the molecular mechanisms that regulate cancer stem cells (CSCs). This will be critical for devising new treatments that selectively target these aggressive and therapy-resistant cancer cells. This will enable us to ultimately translate these findings into the clinic in order to sensitize tumors to conventional therapies by targeting critical regulation of EMT/CSC- pathways by long non-coding RNA mediated epigenetic mechanisms.

简介（由申请人提供）：候选人：Jason Herschkowitz博士在北卡罗来纳大学教堂山分校Charles Perou博士的实验室开始了他的研究生涯。他的研究重点是人类乳腺癌亚型和基因工程小鼠乳腺肿瘤模型的大规模基因组比较。这项研究表明，尽管没有单一的小鼠模型概括了给定人类亚型的所有表达特征，但人类亚型的许多定义特征在小鼠模型中是保守的，这为它们的临床前应用提供了见解。随后，杰森转到贝勒医学院（BCM），在杰弗里·罗森博士的实验室做博士后。在那里，他专注于研究在他的研究生工作中最初发现的低claudin亚型乳腺癌。利用一种独特的小鼠模型，他确定与该模型中出现的其他亚型肿瘤相比，claudin-low肿瘤富含功能性癌症干细胞（CSCs）。Jason的研究生培训为他提供了癌症基因组学和小鼠模型方面的专业知识。他的博士后工作使他在干细胞研究、乳腺发育和肿瘤发生方面拥有丰富的知识和技能。Jason的短期职业目标是现在将他所学到的知识应用到长链非编码rna （lncRNAs）领域。为了接受这一新领域的培训，Jason已经确定了另外两位杰出的共同导师Howard Chang博士和George Calin博士。未来两年的目标是让Jason接受额外的研究培训，以解决这个新的研究领域，以及宝贵的职业指导，为他在一个高排名的学术机构成为一名成功的独立研究者做好准备。环境：杰森是分子和细胞生物学系杰弗里·罗森博士实验室的博士后，该实验室隶属于丹·邓肯癌症中心和莱斯特和苏·史密斯乳房中心的乳房研究项目。BCM为学员培养成为成功的独立研究人员所需的技能提供了良好的环境。学院拥有优秀的教师、中心和最先进的核心设施。BCM位于德克萨斯医疗中心的心脏，步行即可到达几个优秀的研究和临床机构，包括md安德森癌症中心，UT休斯顿医学院，莱斯大学和卫理公会医院研究所。这些机构是额外的科学资源、合作来源和研讨会。研究：基因表达谱已被用于将人类乳腺肿瘤分类为不同的、临床相关的亚组，包括一种罕见的分子亚型，称为claudin