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

项目摘要/摘要 侯选人 杰森·赫施科维茨博士开始了他的研究生涯，当时他是斯坦福大学实验室的一名研究生。 查尔斯·佩鲁在北卡罗来纳大学教堂山报道。他的研究重点是大规模的人类基因组比较 乳腺癌亚型和基因工程小鼠乳腺肿瘤模型。这项研究表明， 虽然没有一个单一的小鼠模型概括了给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提供洞察力的小鼠模型中是保守的 用于临床前应用。杰森随后进入贝勒医学院(BCM)攻读博士后 杰弗里·罗森博士实验室的奖学金。在那里，他专注于研究克拉丁-低亚型 乳腺癌最初是在他的研究生工作中发现的。使用一种独特的老鼠模型，他已经确定 与其他类型的肿瘤相比，克拉丁低的肿瘤富含有功能的肿瘤干细胞(CSCs) 在这种模式下产生的。贾森的研究生培训为他提供了癌症基因组学方面的专业知识和 老鼠模型。他的博士后工作使他获得了参与干细胞研究的知识和技能， 乳腺发育和肿瘤发生。杰森的短期职业目标是现在拿他想要的 已经学习并将其应用于长非编码RNA(LncRNAs)领域。为了接受这方面的培训 在New Area，Jason又找到了另外两位杰出的合作导师：Howard Chang博士和George博士 卡林。未来两年的目标是让杰森接受必要的额外研究培训 攻克这一新的研究领域以及宝贵的职业指导，为他的成功职业生涯做好准备 一位排名靠前的学术机构的独立调查员。 环境 杰森是杰弗里·罗森博士实验室的博士后研究员，供职于分子与科学学院 细胞生物学，丹·L·邓肯癌症中心和莱斯特大学乳房研究计划的一部分 苏·史密斯乳房中心。BCM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。该学院拥有杰出的教员、中心和最先进的技术。 核心设施。BCM位于德克萨斯医疗中心的中心，步行即可到达几个 杰出的研究和临床机构，包括安德森癌症中心、德克萨斯大学休斯顿医疗中心 学校、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 基因表达谱已被用来将人类乳腺肿瘤分类为不同的，临床上... 相关亚群，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肿瘤的紧密连接和黏附连接基因的表达较低，包括 Claudin 3和E-钙粘附素与上皮向间充质转化相关的高表达 基因。我们最近发现，克拉丁低的肿瘤富含功能性的CSCs。已经确定了 在人乳腺上皮细胞中诱导EMT使其具有干细胞样的特性。同舟共济 这些证据表明EMT和CSC富集物之间存在重要的分子和生物学联系 克拉丁低位肿瘤。 最近的研究表明，大多数基因组都是转录的，尽管只有不到2%的 哺乳动物基因组被编码区占据。这些转录本被称为非编码RNA(NcRNAs) 因为它们没有蛋白质编码能力。一直以来，人们都在关注一类人的角色 小的ncRNAs，称为miRNAs，与发育和癌症有关。相比之下，人们对广袤的 大部分转录本由lncRNAs代表。最近的一个主题是许多lncRNA通过 与染色质修饰复合体的相互作用和控制染色质结构。而各式各样的 LncRNAs的功能作用在许多生物过程中都有牵连，只是在相对较少的情况下 这些都有很好的定义吗？LncRNA功能的确切机制细节仍然是一个谜 需要探索。正如可以从lncRNAs在转录调控中的作用中预期的那样，表观遗传学 随着修饰和发展，越来越多的证据表明，在癌症中lncRNAs的错误调控。 包括我们在内的几个研究小组已经表明，乳腺CSCs对辐射和 化疗与非CSCs的比较。我们假设lncRNAs在EMT基因中起关键作用 表达程序部分受RNA介导的表观遗传调节所控制，导致对 乳腺癌的传统治疗方法。对分子网络的更好理解 EMT/CSC表型对于确定对抗CSCs治疗耐药的靶点至关重要，它 可能尤其与克拉丁低的肿瘤有关。这个项目的目标是，使用几个模型系统和一个 大规模功能筛选的策略是首先确定并研究其作用机制 调节低位乳癌EMT/CSC表型的IncRNAs。

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.