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: 8540151
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540151
• 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; 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; screening; 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.

描述（由申请人提供）：候选人：贾森赫什科维茨博士开始了他的研究生涯作为一个研究生在查尔斯佩鲁博士的实验室在圣查佩尔山。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，为它们的临床前应用提供了见解。杰森随后搬到贝勒医学院（Baylor College of Medicine，简称贝勒医学院），在杰弗里罗森博士的实验室担任博士后研究员。在那里，他专注于研究最初在他的研究生工作中发现的乳腺癌的claudin低亚型。使用一种独特的小鼠模型，他已经确定，与该模型中产生的其他亚型的肿瘤相比，claudin低肿瘤富含功能性癌症干细胞（CSC）。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获得了干细胞研究、乳腺发育和肿瘤发生方面的知识和技能。Jason的短期职业目标是将他所学到的知识应用于长链非编码RNA（lncRNA）领域。为了接受这一新领域的培训，Jason又确定了两位杰出的共同导师：霍华德·张博士和乔治·卡林博士。未来两年的目标是让Jason接受必要的额外研究培训，以解决这个新的研究领域，以及宝贵的职业导师，为他在一个高排名的学术机构作为独立调查员的成功职业生涯做好准备。 工作环境：杰森是杰弗里罗森博士实验室的博士后研究员，该实验室是丹L。邓肯癌症中心和莱斯特和苏史密斯乳腺中心的乳腺研究项目。EMBA是一个优秀的环境，让学员发展必要的技能，成为成功的独立研究人员。该学院拥有卓越的教师，中心和最先进的核心设施。酒店位于德克萨斯州医学中心的中心地带，步行即可到达几个优秀的研究和临床机构，包括医学博士。安德森癌症中心，德州休斯顿医学院，赖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，合作和研讨会的来源。 研究：基因表达谱已被用于将人类乳腺肿瘤分为不同的临床相关亚组，包括称为claudin的罕见分子亚型。 低与其他亚型的肿瘤相比，低密蛋白肿瘤具有较低的紧密连接和粘附连接基因（包括密蛋白3和E-钙粘蛋白）表达，以及较高的上皮间质转化（EMT）相关基因表达。我们最近发现，claudin低肿瘤富含功能性CSC。已经确定，在人乳腺上皮细胞中诱导EMT赋予它们干细胞样特性。这些证据表明EMT和CSC富集的低密蛋白肿瘤之间存在重要的分子和生物学联系。 最近的研究表明，大部分的基因组被转录，即使不到2%的哺乳动物基因组被编码区占据。这些转录物被称为非编码RNA（ncRNA），因为它们没有蛋白质编码能力。有大量的关注一类小的ncRNA，称为miRNA，在发育和癌症中的作用。相比之下，对以lncRNA为代表的绝大多数转录物的了解要少得多。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来发挥功能。虽然lncRNA的各种功能作用已经涉及许多生物过程，但只有在相对较少的情况下才能很好地定义。lncRNA功能的精确机制细节仍然是一个需要探索的谜。正如从lncRNA在转录调节、表观遗传修饰和发育中的作用所预期的那样，越来越多的证据表明lncRNA在癌症中的失调。 包括我们在内的几个研究小组已经表明，与非CSC相比，乳腺CSC对放疗和化疗的抵抗力更强。我们假设lncRNA在EMT基因表达程序中起关键作用，该程序部分由RNA介导的表观遗传调控控制，导致乳腺癌对常规治疗产生耐药性。对负责EMT/CSC表型的分子网络的更好理解对于定义用于对抗CSC的治疗抗性的靶点是至关重要的，这可能与低密蛋白肿瘤特别相关。该项目的目标是使用几种模型系统和大规模功能筛选策略，首先确定然后研究调节claudin-low乳腺肿瘤EMT/CSC表型的lncRNA的作用机制。